Monitoring International Trends
posted June 2013
The NBA monitors international developments that may influence the management of blood
and blood products in Australia. Our focus is on:
 Potential new product developments and applications;
 Global regulatory and blood practice trends;
 Events that may have an impact on global supply, demand and pricing, such as changes
in company structure, capacity, organisation and ownership; and
 Other emerging risks that could potentially put financial or other pressures on the
Australian sector.
A selection of recent matters of interest appears below.
Table of Contents
Products................................................................................................................................ 1
Regulatory matters ................................................................................................................ 4
Market structure and company news ..................................................................................... 5
Country- specific events ........................................................................................................ 6
Safety and Patient Blood Management ................................................................................. 7
Research…… ………………………………………………………………………………… … 10
Infectious Diseases ............................................................................................................. 11
Appendix: Alzheimer’s Research ........................................................................................ 14
1. Products
Here the NBA follows the progress in research and clinical trials that may within a
reasonable timeframe make new products available, or may lead to new uses or changes in
use for existing products.
Clotting factors
a) Bayer stopped a Phase II/ III trial of its experimental drug BAY 86-6150 on certain
haemophilia A and B patients due to safety concerns. Bayer had hoped to help
achieve better control of the disease for patients with inhibitors.
b) Novo Nordisk announced the completion of a new study underlining the benefits of
the investigational haemophilia B therapy N9-GP. Paradigm 2 was the first Phase III
trial to assess the long-acting glycolpegylated recombinant factor IX derivative and
showed that N9-GP was able to regulate the frequency of bleeding incidents, while
also enhancing patients' quality of life. No patients developed inhibitors. There were
no apparent differences between the treatment groups in terms of adverse events
and standard safety parameters. The two remaining Phase III trials in the Paradigm
programme respectively involve children and patients undergoing surgery. They are
due to be completed within the next year, with regulatory submissions in 2015.
1
Immunoglobulin
c) Baxter reported on the Phase III study of Gammagard (intravenous immunoglobulin,
IVIg) in Alzheimer’s disease. Gammagard failed to produce an improvement (against
primary endpoints) over placebo in two groups dosed differently over 18 months –
one group receiving 400 mg/kg and the other 200 mg/kg. There was no statistically
significant slowing in cognitive decline or improvement in function, the dual measures
for efficacy set by the US Food and Drug Administration (FDA)--a traditional trial
standard that is now being modified1.
i) A pre-specified subgroup analysis showed some limited benefit in patients
classified as having moderate disease, carrying the gene ApoE4, and treated
with the higher dose. Further analysis may generate a hypothesis for possible
further study, but the results of any resulting trials may be several years out.
ii) Interestingly, Baxter discerned potential in patients with a moderate case; rather
than the early-stage patients which Eli Lilly believed its drug solanezumab
benefited in its failed trial, and for whom it would also need to conduct a new
study if it wants FDA approval.
iii) Soon after the news from Baxter, US firm AttorneyOne was actively offering
expert opinion for legal counsel in potential cases of side effects.
d) Baxter International and Halozyme Therapeutics announced that the European
Commission has granted Baxter marketing authorization in all European Union (EU)
member states for the use of HyQvia (solution for subcutaneous use) as replacement
therapy for adult patients with primary and secondary immunodeficiencies. Baxter will
launch HyQvia in some countries during 2013, and extend to other EU countries in
2014. The product is a combination of human normal immunoglobulin (IgSC, 10%)
with recombinant human hyaluronidase, to facilitate its dispersion and absorption.
The application was based on results from a Phase III, prospective, open-label, noncontrolled multi-centre clinical trial, which evaluated the safety and effectiveness of
HyQvia in the prevention of acute serious bacterial infections, and also the
pharmacokinetic parameters compared with IVIg2.
e) Researchers report that IVIg prophylaxis should be considered as a supplementary
infection control for enteroviral infection outbreaks in nurseries3. “Administration …..
to contacts of infants actively shedding enterovirus during a hospital nursery outbreak
may attenuate severity of disease in those contacts and aid in containment of the
outbreak,” they wrote.
f) Momenta Pharmaceuticals’ President and CEO, in the company’s first quarter 2013
earnings call, recalled the company had in 2012 “successfully demonstrated the
sialylating4 Fc-linked glycans of IVIg antibodies to enhance anti-inflammatory effects
in the preclinical model”. He continued: “In 2013, our first objective is to investigate
1
The FDA is reconsidering the standards of Alzheimer's drug development, contemplating new rules
to encourage investigations in early-stage patients--who may be more likely to respond. The FDA
focus is more on cognition, sacrificing improvement in function if there is benefit to cognition.
2
The study objective was to infuse a 3-or 4-week dose of the treatment in a single subcutaneous site.
The rate of validated acute serious bacterial infections in the study was 0.025 per patient per year,
less than the required efficacy threshold of 1.0 (serious bacterial infections per patient per year). The
most frequently reported adverse reactions to HyQvia were infusion site reactions (20 per cent of
infusions), headache (3 per cent of infusions), fatigue (1 per cent of infusions) and fever (1 per cent of
infusions).
3 Fuchs I. Clin Pediatr. 2013;doi:10.1177/0009922813484087.
4 For an earlier discussion of sialylation in relation to immunoglobulin, see Johannes Stadlmann,
Martin Pabst, and Friedrich Altmann, “Analytical and Functional Aspects of Antibody Sialylation” J Clin
Immunol. 2010 May; 30(Suppl 1): 15–19. Published online 2010 April 14. doi: 10.1007/s10875-0109409-2
2
the biology of sialylated IVIg to inform our selection of the best indications to take
forward into our initial clinical proof-of-concept trial. Our second objective is to define
a specific product or products we will consider presenting into the clinic….there are
two ways to apply the technology of sialylated, plasma-derived IVIg product or a
recombinant sialylated Fc product. We are investigating both approaches and expect
to have data later this year that will help guide our development efforts”.
Other
g) At the annual meeting of the American Thoracic Society (ATS) in May Grifols
presented results from a study of its Prolastin-C (Alpha1-Proteinase Inhibitor
[Human]) in patients with alpha1antitrypsin (AAT) deficiency5. The Prolastin-C
SPARK study was a multidose pharmacokinetic clinical trial. The trial demonstrated
that weekly infusions of PROLASTIN-C at 120 mg/kg increased serum
concentrations of the A1PI protein to proportionately higher levels than weekly
infusions of 60 mg/kg, the approved dose of PROLASTIN-C. The 120 mg/kg dose
raised serum concentrations of A1PI to the range of considered to be normal for
healthy individuals. Both doses were safe and well tolerated in subjects with AAT
deficiency.
i) The SPARK study is the basis for Grifols to proceed with a larger, long-term
study of the two doses of PROLASTIN-C. This SPARTA trial will evaluate the
efficacy of PROLASTIN-C at the standard 60/mg/kg dose and the 120 mg/kg
dose vs. placebo. The study will use CT lung densitometry to measure the
degree of lung tissue preservation over time. This multi-centre trial will begin in
the second half of 2013.
h) Acceleron scientists received an award for best abstract and oral presentation at the
12th International Symposium on Myelodysplastic Syndromes in Berlin in May. They
presented data on the effects of the protein therapeutic, ACE-536, on correcting
anaemia and ineffective erythropoiesis in an animal model of myelodysplastic
syndromes (MDS). In a separate poster presentation, Acceleron described its
ongoing Phase II study of ACE-536 in patients with MDS. ACE-536 increases red
blood cells and haemoglobin levels through a different mechanism from that of
currently available anaemia therapies, such as erythropoiesis-stimulating agents.
Synthetic blood and platelets
i) Researchers at the Scottish Centre for Regenerative Medicine (SCRM) in Edinburgh
have been working with stem cells to produce blood on an industrial scale. Now the
UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has granted
them a licence to test blood made from stem cells in humans.
i) The researchers initially based their work on embryonic stem cells, which was
controversial. They are now turning their attention to using stem cells from adult
donors.
ii) The licence allows work to begin at the SCRM’s new GMP (good manufacturing
practice) Cellular Therapy Manufacturing Facility. This is jointly operated by the
Scottish National Blood Transfusion Service (SNBTS) and the company Roslin
Cells.
iii) The project leader is Professor Marc Turner, director of SNBTS.
j) Researchers in Cleveland, Ohio, are developing plastic-coated synthetic platelets to
be injected by first responders to wounded soldiers or crash victims bleeding
internally6. These portable platelets are nanoparticles designed to stick to natural
platelets and leverage quicker and more efficient clotting at the site of an internal
5
AAT deficiency is a life-threatening, genetic condition in which low levels of the alpha 1 proteinase
inhibitor (A1PI) protein can lead to emphysema.
6
The project is headed by Erin Lavik, associate professor in biomedical engineering at Case Western
Reserve University.
3
wound. The nanoparticles are spheres made from material used in dissolvable
sutures, and they disappear from the body after doing their work. They have an
outer coating of polyethylene glycol. Scientists attach to them a peptide, or small
piece of protein, that adheres to platelets. The product is a white powder with a shelflife of at least two weeks without refrigeration. The powder would be mixed with
water and then injected. Testing has not yet been conducted on humans.
2. Regulatory
The NBA monitors overseas regulatory decisions on products, processes or procedures
which are or may be of relevance to its responsibilities.
a) The FDA in May accepted for review Biogen Idec’s Biological License Application
(BLA) for marketing approval of Eloctate (recombinant factor VIII Fc fusion protein) for
the treatment of haemophilia A. Eloctate is the first of a new class of long-lasting FVIII
products. In March the FDA accepted for review the BLA for Biogen’s FIX candidate,
Alprolix, for haemophilia B.
b) Boehringer Ingelheim announced three updates to the US prescribing information for
its oral anticoagulant (OAC) Pradaxa. The label now carries a boxed warning, similar
to the warnings in the labels of other new OACs, to advise patients that discontinuing
treatment puts them at increased risk of stroke. The post marketing experience
section of the Pradaxa label has been updated to include thrombocytopenia.
c) AbbVie and Intermune filed requests for an injunction to prevent the European
Medicines Agency (EMA) from releasing detailed patient-level data from studies
about their drugs. They are the first to challenge a three-year-old agency policy to
provide access to documents and were made in response to a pair of freedom of
information requests made to the EMA last year to release “raw data” on safety and
efficacy. AbbVie is trying to prevent rivals from obtaining data about its Humira
treatment for rheumatoid arthritis. The General Court of the EU has ordered the EMA
not to provide any documents to the drug makers that filed the freedom of information
requests, at least until a final ruling is given. The EMA says it is considering whether
to file an appeal. It will continue releasing documents on a case-by-case basis,
depending upon the outcome of these challenges. Since November 2010, more than
1.9 million pages of documents have been released in response to requests. The
EMA, having published on its website the final advice it received from five
stakeholder advisory groups on clinical data transparency, says it will have its draft
policy out for consideration by the end of June 2013.
d) Hemopure, the oxygen carrier made from bovine haemoglobin by OPK Biotech in
Cambridge Massachusetts, was approved by the FDA for compassionate use for a
Jehovah’s Witness in Kansas who was bleeding internally.
e) In May, Amag announced that its partner Takeda Pharmaceutical was taking a batch
of its drug ferumoxytol (Feraheme) off the market in Switzerland. Four patients had
experienced severe allergic reactions, and one of those had died. That batch was
sold only in Switzerland.
i) The FDA approved the drug in 2009, as a treatment for iron deficiency anaemia.
In the US it is approved for use in patients with chronic kidney disease.
ii) EU regulators approved the drug in 2012 under the name Rienso. Takeda
markets the drug in Europe.
iii) Severe allergic reactions are a side effect common to several anaemia drugs.
Early this year Affymax and Takeda withdrew their anaemia drug Omontys from
the market after several patients died and about 50 had severe allergic reactions.
The FDA had approved Omontys in March 2012.
f) Combat Medical Systems (CMS), of North Carolina, received new FDA indications
for its Combat Ready Clamp. It is approved for controlling haemorrhaging in ”every
compressible, junctional emergency situation. It can be applied in under a minute
4
and works on areas of the body and in circumstances where standard tourniquets are
not applicable and manual pressure is not enough, such as severe pelvic wounds. It
is designed to prevent slipping during and after tightening and will work on people of
most sizes. CMS has worked with the US Army’s Institute for Surgical Research in
San Antonio, Texas, and with the Wake Forest University Baptist Medical Center in
Winston Salem, North Carolina, on clinical efficacy of the device. The clamp has had
some use in Afghanistan and in Life Flight cases in the US.
3. Market structure and company news
The NBA’s business intelligence follows company profitability, business forecasts, capital
raisings or returns, mergers and takeovers, arrangements for joint research and/or
development, contracts for supply of manufacturing inputs, and marketing agreements.
Companies considered include suppliers, potential suppliers and developers of products
which may be of interest.
a) Kedrion has downsized a previously announced expansion of its Melville plant.
Kedrion will now add 18,000 square feet instead of 48,000 square feet to the existing
structure of 105,000 square feet of space, reducing construction costs from $US23
million to $US 7.5 million, and equipment purchases to $US15 million rather than
$42 million. The company expects to create 30 jobs, not the 80 promised last year in
return for government aid. The company still plans to retain 150 workers it will inherit
by purchasing the factory from Grifols, under arrangements required by the US
Federal Trade Commission as a condition of its approval of Grifols’ takeover of
Talecris. The letter to Suffolk County on the smaller expansion referred to "less
funding than initially anticipated from [Kedrion's] Italian parent." Last year Kedrion
officials said the work done locally could be done in Italy. Kedrion will now receive
only $US 1.9 million in tax breaks from the county's industrial development agency,
not $US 4.8 million. Incentives from other agencies will also be adjusted
proportionally.
b) For Cerus Corporation, product revenue for the first quarter of 2013 was $ US9.7
million, a 12 per cent increase over the first quarter of 2012. Gross margins on
product sales for the first quarter of 2013 were 48 per cent, compared with 37 per
cent for the first quarter of 2012. This reflected lower average costs for products sold
as a result of higher manufacturing levels.
c) Aalborg University Hospital, Denmark, signed a five year project collaboration
agreement for Cerus’ INTERCEPT Blood System for platelets.
d) NuSep raised $A 350,000 via a placement of shares with a Singapore-based
investor. This provided the company with working capital while it finalises
investments in its plasma fractionation business, PrIME Biologics, which is building a
plasma fractionation facility in Singapore. It will use NuSep’s PrIME Technology in its
therapeutic plasma manufacturing process and is concentrating on opening up the
Asian therapeutic plasma market, particularly the untapped Currently Unprocessable
Plasma (CUP) market. The company plans to produce around 150,000 litres of
human therapeutic products per year.
e) Novo Nordisk’‘s first-quarter 2013 profit rose 28 per cent compared with Q1 2012 ,
boosted by higher sales in the diabetes market. Revenue from NovoSeven grew by 6
per cent.
f) Baxter’s announcement of disappointing trial results of Gammagard in Alzheimer’s
disease led to a fall not only in its share price, but in the share prices of CSL and
Grifols as well.
g) Grifols’ net profit rose 19 per cent in the first quarter of 2013 from the first quarter a
year ago, boosted by overseas sales, especially in Latin America and Asia. The
5
company generates over 90 per cent of its sales outside its recession-hit home
market.
h) Grifols’ ordinary general shareholders’ meeting in May was told that debt reduction
remains a priority. The meeting confirmed support for the company’s focus on
international growth, securing production capacities and the technical and human
resources necessary to ensure organic growth, and promoting new strategic
research and development, including a global and comprehensive approach to
Alzheimer's disease.
i) Grifols and Aradigm Corporation signed a worldwide licensing agreement to develop
and commercialize Pulmaquin, Aradigm's proprietary inhaled ciprofloxacin
formulation for patients with severe respiratory disease.
j) Grifols inaugurated a new immunoglobulin plant in Los Angeles. The new plant has
an annual initial purification capacity of 8 million grams of IVIg. Grifols says it plans
to invest another $US 70 million over the next two years at the Los Angeles complex.
4. Country- specific events
The NBA is interested in relevant safety issues which arise in particular countries, and also
instances of good practice. We monitor health issues in countries from which Australia’s
visitors and immigrants come.
Canada
a) Canada is removing its barrier of almost three decades against gay men donating
blood. The new policy will allow them to donate blood if they have not had sex with
another man for five years.
b) The province of Ontario issued suspension notices to thousands of high school
students who lacked proof of vaccination against measles, mumps, rubella, polio,
diphtheria, and tetanus. Laws in Manitoba and New Brunswick require vaccination
records as a prerequisite for school attendance, as do all fifty states in the US.
United States
c) The Immunoglobulin Nursing Society (IgNS) announced the development of the first
certification program for immunoglobulin nurses. Its goal is to demonstrate
competence and standardization of immunoglobulin nursing practice.
d) In January 2011 the US introduced the Medicare prospective payment system
(“bundling”) for dialysis-related care and in June 2011 there were changes in labelling
of erythropoiesis-stimulating agents (ESAs). Two recent studies7 offer further
evidence of a trend toward decreasing use of ESAs, decreasing haemoglobin levels
and higher blood transfusion rates. Because transfusions are excluded from
bundling, there is a potential for increased use of transfusions to supplement ESA
use.
e) LifeStream, which provides blood products to hospitals in southern California, is now
offering blood donors free cholesterol screening with every donation. A total count of
“good” and “bad” cholesterol will be given.
f) The US government has signed an antibiotics development deal with GlaxoSmithKline
(GSK). GSK will collaborate with the Biomedical Advanced Research and
Development Authority (BARDA), part of the Department of Health and Human
Services, to study potential new drugs to treat conventional pathogens and also those
that could be developed into weapons.
g) The US Centers for Disease Control and Prevention (CDC) in May published results
of its Dialysis Bloodstream Infection Prevention Collaborative showing that when CDC
prevention guidelines were followed there was a 32 per cent decrease in overall
7
Presented to the National Kidney Foundation 2013 Spring Clinical Meetings
6
bloodstream infections and a 54 per cent decrease in vascular access-related
bloodstream infections8.
United Kingdom
h) A new risk assessment published this month by UK government team says there is
still a risk of people contracting variant Creutzfeldt-Jakob Disease (vCJD) through
blood transfusions, as about 30,000 residents are likely to be carriers. In a high case
scenario, they suggest that infected blood donations could cause up to 1,000 deaths,
some in people who have already received blood transfusions. The report suggests
ministers could consider recruiting young blood donors who will not have eaten
infected beef.
i) Researchers at Imperial College London have found that patients undergoing nonemergency operations on a Friday are 44 per cent more likely to die than those
having their surgery on a Monday. Their research, which looked at data from more
than four million elective procedures conducted in NHS hospitals in England between
2008 and 2011, was published in the British Medical Journal. One of the questions
these results raised was the quality of hospital care over the weekend,
Ireland
j) A report by the Irish Medicines Board is critical of the speed with which some incident
reports and complaints about blood products have been dealt with by the Irish Blood
Transfusion Service (IBTS), as well as the documentation in relation to investigations.
The inspection was also critical of some aspects of the IBTS’s blood-collection policy,
in particular the collection of blood from people with low haemoglobin levels. The
report says the policy of collecting blood from people with a haemoglobin level of 1212.4 g/dl (males) or 13-14 g/dl (females) was below that specified in national and
European legislation. The management of donors with multiple deferrals for low
haemoglobin “was not considered robust”, according to the inspection report. IBTS
undertook to introduce an information leaflet for donors who are deferred for a low
haemoglobin count.
k) Positive Action Ltd, which advocates for women who received blood products
contaminated with Hepatitis C, lost a High Court action over the way it is funded by
the Health Service Executive.
Australia
l) On the night of May 11, Canberra’s Questacon building and the Telstra Tower turned
“lime” green to raise awareness in the community and by doctors of Lyme disease.
The awareness campaign would also see green buildings in Brisbane, Sydney,
Melbourne, Adelaide and Perth9.
Indonesia
m) In Indonesia, the government-owned pharmaceutical firm PT Indofarma plans to begin
producing albumin locally this year. Its collaborators will be the Indonesian Red
Cross (PMI), a private partner, and a European firm.
8
The study was published in the American Journal of Kidney Diseases, the study examined at data
reported to the National Healthcare Safety Network (NHSN) by 17 outpatient dialysis facilities. CDC
interventions included chlorhexidine for catheter exit-site care, staff training and competency
assessments focussed on catheter care and aseptic technique, hand hygiene and vascular access
care audits, and feedback of infection and adherence rates to staff.
9
The Australian Broadcasting Commission in May aired a programme on Lyme disease, which
reported that
 “a growing number of Australian GPs are risking their professional reputations by diagnosing
patients with Lyme disease”;
 “health authorities say there’s no evidence that Australian ticks carry the Lyme bacteria”; and
 “the nation’s chief medical officer has formed an advisory committee to look into this
controversial disease”
7
5. Safety and patient blood management
We follow current issues in patient safety.
a) A study10 of over two thousand patients treated for bladder cancer with a radical
cystectomy found worse outcomes in those who received a perioperative blood
transfusion. Patients who received a transfusion were significantly older than those
who did not and were more likely to have muscle-invasive tumors. The team
recognized that the mechanism by which transfusion may affect cancer-related
outcomes has not been definitively established, but one theory is that an
immunosuppressive effect of the transfusion may reduce host tumour surveillance.
b) The European Heart Rhythm Association (of the European Society of Cardiology)
has issued practice guidelines for the use of the oral anticoagulants dabigatran,
rivaroxaban, apixaban and edoxaban in patients with atrial fibrillation. The guidelines
cover clinical scenarios and advice on managing bleeding risks.
c) A recent trial concluded that preoperative antithrombin supplementation in cardiac
surgery prevents heparin resistance and avoids excessive postoperative decrease of
antithrombin activity11.
d) A protocol has been proposed to correct pre-operative anaemia using a single, high
dose of recombinant human erythropoietin (HRE) administered only two days prior to
surgery. The results of a randomized study were presented by Luca Weltert, of the
Cardiac Surgery Department of the European Hospital in Rome, at the American
Association for Thoracic Surgery Annual Meeting in May12. In this single-blind
randomized study of 600 patients having cardiac surgery, 300 patients received a
single dose of HRE 80,000 IU two days before their surgery. Prior administration of
HRE reduced transfusion requirements by about one third. Mean haemoglobin levels
on postoperative day 4 were significantly higher in the HRE group. No differences
between groups were found for mortality or adverse events.
e) An Australian inquest has found three women died within a month of receiving
transplanted organs from the same donor who passed on a rare mouse-borne virus.
The donor died from a stroke soon after returning to Melbourne following a stay with
relatives in Serbia. It appears the donor’s family was not asked about his health
issues before they donated his organs. Lymphocytic choriomeningitis-like virus
[LCMV-like] virus had not previously been detected in Victoria.
f) An international team of economists, writing in the journal Science, says countries
that prohibit monetary incentives to blood donors may want to modify their position,
based on recent research. They say studies based on behaviour suggest incentives
may attract more donors. So as not to encourage potential donors who might
misrepresent their health status, they say the reward should not be for an actual
donation but for turning up to a donor centre.
g) FDA scientists at the Center for Biologics Evaluation and Research (CBER) have
reported that animal studies provide a proof of concept that patients whose lungs are
already inflamed could potentially suffer further lung damage if they receive a
transfusion of platelets that were exposed to ultraviolet B (UVB) light. Their study
was a response to an observation in a clinical trial that some patients who were
10
led by Stephen A. Boorjian, of the Mayo Clinic in Rochester, Minnesota and reported in the May
2013 issue of Renal And Urology News
11
Marco Ranucci, Ekaterina Baryshnikova, Giulia Beatrice Crapelli, Michael K. Woodward, Antonio
Paez, and Gabriele Pelissero: “Preoperative antithrombin supplementation in cardiac surgery: A
randomized controlled trial” Thorac Cardiovasc Surg 2013;145:1393-1399
12 "Single High Dose of Erythropoietin Two Days Before Surgery: A Simplified Short Term Approach
to Blood Spare," by Luca Weltert, MD, Beatrice Rondinelli, MD, Mauro Falco, MD, Alessandro
Bellisario, MD, Daniele Maselli, MD, Luca Pierelli, MD, and Ruggero De Paulis, MD. Presentation at
the 93rd AATS Annual Meeting. May 4-8, 2013. Minneapolis, MN, during the Plenary Scientific
Session on May 6. Reported May 6, 2013 in Surgery.
8
transfused with platelets treated with UV light and a photosensitizing chemical to
reduce the presence of viruses and bacteria appeared more likely to develop sudden
respiratory distress13.
h) A study published in the June issue of the Annals of Thoracic Surgery suggests that
patients transfused with red blood cells during or after cardiac surgery may have a
higher risk of infection. The lead author was Dr Keith Horvath, of the US National
Heart, Lung, and Blood Institute. The observational study was conducted by the
Cardiothoracic Surgical Trials Network and involved 5,200 adults who had cardiac
surgery of various types in a number of institutions; 48 per cent were transfused with
red blood cells and 31 per cent were given platelets. With each red blood cell unit
administered, there was a 29 per cent increase in infection risk. However, platelets
transfused together with over four units of red cells was associated with a lower
infection risk.
i) IVIg has been associated with the risk of stroke since the 1980’s. Now Wake Forest
University School of Medicine researchers have looked at a group of 16 patients, 14
of whom experienced a stroke during treatment or within 24 hours. The other two
had a stroke within four days. The researchers found fifteen of the sixteen had at
least one risk factor for stroke, such as diabetes or high blood pressure. They
concluded that although the risk of IVIg linked stroke is small – 0.6 per cent of
patients over a four year period they found- those who are at risk should be identified
before treatment.
j) The May 25 issue of The Lancet discussed best practices in blood transfusion,
alternatives to allogeneic transfusion, and challenges in managing blood supply.
i) Laurence T. Goodnough from Stanford University and colleagues reviewed best
transfusion practices among adults. They noted variability in transfusion
outcomes in clinical settings such as cardiothoracic surgery, and postulated that
this could result from poor understanding of published guidelines and
recommendations from professional bodies. They commented that best
practice increasingly means a restrictive approach to blood transfusion.
ii) Donat R. Spahn, from the University Hospital of Zurich, and Goodnough,
examined alternatives to allogeneic blood transfusion, suggesting that cost and
outcomes will drive the selection of blood alternatives such as autologous blood
procurement, erythropoiesis-stimulating agents, and haemostatic agents.
iii) Lorna M. Williamson, from the UK’s National Health Service Blood and
Transplant, and Dana V. Devine, from Canadian Blood Services in Vancouver,
described the challenges in managing blood supply in developed countries with
ageing populations.
k) Johns Hopkins researchers have prepared new guidelines to optimize the process
of preoperative blood ordering14. The previous maximum surgical blood order
schedule (MSBOS) was developed in the late 1970s, since when new surgical
procedures have been introduced and others modified.
i) The new institution- specific schedule was developed using blood use data from
the hospital’s electronic anaesthesia information management system for
53,536 patients in 1,632 surgical procedures. An algorithm based on previously
defined criteria15 was used to develop an MSBOS for each surgical specialty.
Monique P. Gelderman, Xuan Chi, Li Zhi, and Jaroslav G. Vostal ,“Ultraviolet B light-exposed
human platelets mediate acute lung injury in a two-event mouse model of transfusion”,
Transfusion,2011, 51:2343-2357
14
Frank, Steven M.; Rothschild, James A.; Masear, Courtney G.; Rivers, Richard J.; Merritt, William
T.; Savage, Will J.; Ness, Paul M. “Optimizing Preoperative Blood Ordering with Data Acquired from
an Anesthesia Information Management System”, Anesthesiology, June 2013 - Volume 118 - Issue 6
- p 1286-1297 doi: 10.1097/ALN.0b013e3182923da0
15
the per cent of patients transfused, the median estimated blood loss, the transfusion rate, and the
risk of major bleeding. Surgeries with low transfusion rates included breast procedures,
13
9
The authors said optimizing perioperative blood ordering improved theatre
efficiency, increased patient safety and decreased costs.
ii) Steven Frank of Johns Hopkins said that in three out of every 1,000 cases the
algorithm may not guess correctly, but O-negative blood can be procured within
minutes with minimal risk of patient harm. If those patients had substantial
anaemia before surgery blood should be ordered in any case.
6. Research
a) Chemotherapy is known to cause peripheral neuropathy. Now researchers16 working
with mice have found it also induces nerve damage inside bone marrow, and suggest
that combining nerve protecting drugs with chemotherapy may prevent long- term
bone marrow injury and anaemia, and facilitate successful bone marrow transplants.
b) Scientists from Boston Children's Hospital's Program in Cellular and Molecular
Medicine believe that more than platelets, thrombin and fibrin are required to
construct a deep vein thrombosis (DVT). Neutrophils--cells recognized for their role in
immune defence-- release platelet-catching nets made of chromatin, a mix of DNA
and associated proteins. They found that mice lacking a neutrophil enzyme called
PAD4, which helps unravel the chromatin in neutrophils' nuclei, cannot form DVTs.
This may open the way for more targeted treatments17
c) Researchers reported in the Annals of Pharmacotherapy that in their study blood
thinners were involved in 7 per cent of medication errors.
d) The California Institute for Regenerative Medicine has granted Sangamo
BioSciences a $US 6.4 million Strategic Partnership Award to develop a potentially
curative therapeutic for beta-thalassemia using its zinc finger nuclease (ZFN) geneediting technology in hematopoietic stem cells.
e) Researchers from Boston Children's Hospital have created injectable oxygen
microparticles for patients with breathing impairments. The emergency, IV oxygendelivering syringe contains microparticles of oxygen gas and liquid18.
f) GlaxoSmithKline (GSK) has announced it will release an online system of patient
level data from its trials in an effort to increase scientific understanding. A selection
of independent specialists will review research proposals for access to anonymised
patient level data, with the plans advancing towards a broader system of multiple
organisations via an independent data custodian. Patrick Vallance, GSK’s president
of pharmaceuticals R&D, said: “When people volunteer for clinical trials they expect
that the results will be used to help others. We are absolutely committed to sharing
data so that researchers can examine the details more closely, do their own analyses
and learn more about medicines and how they can best be used.” GSK is currently
holding negotiations with interested parties to promote the development of the
system.
g) Biomedical engineers at Duke University have used pluripotent embryonic stem cells,
which can grow to become any kind of organ with appropriate chemical and physical
signals, to create a 3-dimensional patch of human heart muscle that is as functional
as natural tissue. It may be used to test new medications for heart disease.
h) Canadian scientists, led by Don Brooks from the Centre for Blood Research at the
University of British Columbia, have created an ultra-strong cell membrane adhesive
thyroid/parathyroid procedures, cerebrospinal fluid shunt procedures, cystoscopy/ureter/urethral
procedures, and open shoulder procedures.
16
From the Albert Einstein College of Medicine of Yeshiva University; report published online in
Nature Medicine.
17
Findings were published in the week beginning May 6 in the online early edition of the Proceedings
of the National Academy of Science.
18
Science Translational Medicine, June 27 2012
10
i)
j)
and used it to bind red blood cells to each other19. The polymer could be used in
tissue engineering and wound closure.
Researchers from Yale School of Medicine and University College London have
found the molecular pathway by which new arteries may develop after heart attacks,
strokes and other acute illnesses — bypassing arteries that are blocked20.
A study funded by the US Department of Health and Human Services, and published
May 29 in the New England Journal of Medicine, tested three prevention strategies
for the hospital-acquired infection known as methicillin-resistant Staphylococcus
aureus -- or MRSA. The test was conducted with patients in intensive care units
(ICU): by giving standard care, by giving germ-killing soap and ointment only to ICU
patients with MRSA bacteria, or providing the antibacterial products to all ICU
patients. This third strategy reduced bloodstream infections by up to 44 per cent and
significantly reduced the presence of MRSA. The study involved 74 adult ICUs and
more than 74,000 patients. It was conducted by researchers from the University of
California at Irvine, Harvard Pilgrim Health Care Institute, the Hospital Corporation of
America and the CDC.
7. Infectious diseases
The NBA takes an interest in infectious diseases because: the presence of disease in
individual donors (e.g. influenza), or potential disease resulting from travel (e.g. malaria)
means a donor must be deferred; temporary disease burden within a community (e.g.
dengue in North Queensland) may limit blood collection in the community for a time; and
some people may not be permitted to donate at all (e.g. people who lived in the UK for a
period critical in the history of vCJD). Blood donations are tested for a number of diseases
(e.g. HIV and Hepatitis B), but there are also emerging infectious diseases for which it may
become necessary to test in the future (e.g. Chagas disease, and the tick-borne babesiosis
and Lyme disease).
Mosquito- borne diseases
a) A group of researchers from Duke Medicine and Duke-National University of
Singapore reported that a protein produced by mast cells in the immune system may
predict which dengue patients will go on to develop dengue haemorrhagic fever.
They also demonstrated in mice that a class of drugs which treat asthma by targeting
the mast cells could help treat vascular symptoms associated with dengue21.
b) New Caledonia registered 8,250 cases of dengue in the eight months from
September 2012. Three patients had died. New Caledonia has also had a few
chikungunya cases.
c) Singapore has been experiencing a dengue outbreak which some officials believe
may be the worst ever. The National Environment Agency said 8,000 people had
been infected so far this year, and the peak season is May to October so they expect
to surpass the 2005 epidemic when there were 14,006 confirmed cases (and 27
deaths).
d) By early May, 100 people had been infected by chikungunya in Singapore this year,
up from 3-6 annually for the past 3 years. Unlike dengue, chikungunya is not
considered endemic in Singapore.
e) Takeda will acquire Inviragen for an upfront payment of $US 35million and milestone
payments of up to US$215 million linked to the progress of clinical development and
achievement. Inviragen is a Colorado company engaged in research and
development of innovative vaccines for emerging infectious diseases, including
19
X Yu et al, Chem. Commun., 2013, DOI: 10.1039/c3cc41895b
Reported in the April 29 issue of Developmental Cell.
21
online journal eLife on April 30, 2013
20
11
dengue. DENVax is a four-strain recombinant viral vaccine being evaluated in Phase
II trials. Inviragen’s recombinant vaccine candidate against chikungunya is in
preclinical development.
f) The Guardian Professional asked readers to nominate the best innovations towards
eliminating malaria. The nanomal DNA analyser came in first - nanotechnology is
being used to develop an affordable, easy to use smartphone-like device to analyse
within 15 minutes malaria strain DNA from a finger-prick of blood. Second was a
needleless malaria testing application which uses a light sensor (connected to a
tablet) that is passed over a finger to diagnose malaria.
g) Australian scientists22 have developed a malaria vaccine that can be tailored to
variants of the disease. Human trials of will begin in 2014.
h) Veredus Laboratories has developed a biochip that can identify from a single blood
sample any or many of thirteen major tropical diseases including dengue fever,
malaria, chikungunya, and hand, foot and mouth disease, in the field. Infectious
disease expertise was provided by A*STAR’s Singapore Immunology Network
(SIgN). The biochip operates on STMicroelectronics’ Lab-on-Chip platform.
i) The CDC in May released the final 2012 national surveillance data for West Nile virus
activity. A total of 5,674 human cases, including 286 deaths, were reported from 48
US states (excluding Alaska and Hawaii). 51 per cent were classified as
neuroinvasive disease (e.g. meningitis, encephalitis, or acute flaccid paralysis).
j) By 11 May there had been 128 confirmed cases of dengue in the current outbreak in
Far North Queensland.
Influenza
k) At 7 May the case count for confirmed H7N9, the new strain of avian flu which
emerged in China, was 131. 31 had died. By 29 May the World Health Organisation
(WHO) had been notified of 132 laboratory confirmed cases of whom 37 had died.
While closing live bird markets was assumed to have contributed to the slowing of
the infection rate, there were thought to be seasonal factors involved too. WHO said
there was no evidence of sustained human to human transmission, although a few
cases seemed to have occurred. The source of infection had not been definitively
identified or controlled23.
l) Researchers at China’s National Avian Influenza Reference Laboratory at Harbin
Veterinary Research Institute have deliberately created deadly new strains of
influenza— and are being very severely criticised by others in the wider scientific
community. They mixed the H5N1 bird-flu virus —lethal but not easily transmitted
22
led by Dr Krystal Evans, Professor Louis Schofield and Professor Alan Cowman from the Walter
and Eliza Hall Institute’s Infection and Immunity division, and Professor James McCarthy from the
Queensland Institute of Medical Research. The manufacture and trial of the vaccine is being
supported by an Australian National Health and Medical Research Council (NHMRC) Development
Grant. Early stages of the project were supported by the Bill and Melinda gates Foundation.
23
On the WHO website:- Candidate vaccine viruses for avian influenza A(H7N9) as of 25 May 2013
http://www.who.int/influenza/vaccines/virus/candidates_reagents/a_h7n9/en/index.htmlChina-WHO Joint Mission on Human Infection with Avian InfluenzaA(H7N9) Virus, 18-24 Apr 2013,
Mission Report
http://www.who.int/influenza/human_animal_interface/influenza_h7n9/ChinaH7N9JointMissionReport
2013u.pdf
- Laboratory procedures - serological detection of avian influenza A(H7N9) infections by
microneutralization assay
http://www.who.int/influenza/gisrs_laboratory/cnic_serological_diagnosis_microneutralization_a_h7n9.
pdf http://www.who.int/influenza/gisrs_laboratory/cnic_serological_diagnosis_hai_a_h7n9.pdf>
- Laboratory biorisk management for laboratories handling humanspecimens suspected or confirmed
to contain avian influenza A(H7N9)virus causing human disease - interim recommendations
http://www.who.int/influenza/human_animal_interface/influenza_h7n9/InterimRecLaboratoryBioriskMa
nagementH7N9_10May13.pdf
12
m)
n)
o)
p)
q)
r)
s)
t)
between humans — with a 2009 strain of H1N1 that is very infectious to humans.
They created 127 different viral hybrids — five of which were shown to easily pass
through the air between laboratory guinea pigs. Robert May, former Chief Scientific
Adviser to the UK Government, commented to The Independent:”The record of
containment in labs like this is not reassuring. They are taking it upon themselves to
create human-to-human transmission of very dangerous viruses. It’s appallingly
irresponsible.”
Scientists at Greffex24 believe they've created the first comprehensive vaccine for
H7N9 avian influenza. Safety tests will be conducted over the next 2 to 3 months. If
its found to be safe, clinical trials can begin.
Medicago announced on 8 May that it had successfully produced a virus-like particle
vaccine candidate for H7N9 flu.
Scientists working for Pathology Queensland’s Microbiology Department and the
Queensland Paediatric Infectious Disease Laboratory have developed a test for
H7N9.
A gene mutation which makes flu viruses resistant to Tamiflu was identified in two
patients infected with the H7N9 bird flu virus in China.
Singapore's Agency for Science, Technology and Research (A*STAR) said in May
that the first healthy volunteer had been dosed with the H1N1 influenza vaccine it
had jointly developed with the Switzerland-based Cytos Biotechnology AG in a
clinical trial.
Sanofi researchers in Boston have published results in Nature on a new type of
vaccine for the flu virus that is a step toward developing a universal vaccine25.
Novartis says it has synthesized hybrid flu genomes in a process which could speed
up vaccine production.
Eritoran, a compound under investigation as a sepsis drug, has been found to
decrease substantially deaths from influenza in mice26.
Other
a) In Saudi Arabia’s Eastern province, a cluster of 13 patients in a health care facility
contracted the novel coronavirus which has been of concern for some months. Seven
died. This cluster increases the concern about human to human transmissibility.
WHO is now referring to this as Middle East respiratory syndrome (MERS) and is
seriously concerned about its pandemic potential. The head of WHO, Dr Margaret
Chan, warned late in May that international efforts to combat MERS have been
hampered by unclear rules and competition for the potentially profitable rights to
disease samples. On 30 May the case count of laboratory confirmed cases was 49,
with 27 deaths. Research is continuing on whether there is an animal reservoir for
this virus.
b) A survey conducted by Sanofi Pasteur of 1042 Australians who have travelled
overseas in the past 5 years found more than half did not receive appropriate
vaccinations; in all 2.8 million travellers may not have had the vaccinations
appropriate to their destination. One disease apparently ignored is typhoid - there
were 134 cases of typhoid reported in Australia in 2011, an increase on an average
of about 50 in earlier years. A young Queensland man died of typhoid in January this
year after a visit to the Middle East and southern Asia.
c) In Japan, between January and April this year, 5442 people, have been reported as
having rubella (German measles). Most were males over 20 who had not been
vaccinated.
24
Headquartered in Colorado and in The Netherlands
Kanekiyo M, Wei C, Yassine H, et al.” Self-assembling influenza nanoparticle vaccines elicit broadly
neutralizing H1N1 antibodies”. Nature.2013.
26 Shirley, Vogel et al, “The TLR4 antagonist Eritoran protects mice from lethal influenza infection”, Nature,
published online 1 May 2013. doi:10.1038/nature12118
25
13
d) Two horses in Queensland contracted bat lyssavirus, most probably from a species
of micrbat, not flying foxes.
e) Chimerix presented data showing CMX001's high barrier to viral resistance in the
prevention and treatment of cytomegalovirus (CMV) infection. The data were
presented at the International Society for Antiviral Research's May conference in San
Francisco.
14