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Read the latest articles relevant to your clinical practice, including exclusive insights from Healthed surveys and polls.

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The dementia ‘tsunami’ is coming – but two potential medications offer hope
Dr Linda Calabresi
  • Clinical Articles

Predicting and Preventing Dementia

Adolescent boys who struggle to understand how basic machines work and young girls who have difficulty remembering words are at increased risk of developing dementia when they’re older, new research has found. According to the longitudinal study published in The Journal of the American Medical Association, lower mechanical reasoning in adolescence in boys was associated with a 17% higher risk of having dementia when they were 70. With girls it was a lower memory for words in adolescence that increased the odds of developing the degenerative disease. It has been known for some time that the smarter you are throughout life, even as a child the less likely it is that you will develop dementia. Not a guarantee of protection – just a general trend. It has to do with cognitive reserve, the US researchers explain. “Based on the cognitive reserve hypothesis, high levels of cognitive functioning and reserve accumulated throughout the life course may protect against brain pathology and clinical manifestations of dementia,” they wrote. This theory has been supported by a number of studies such as the Scottish Mental Health Survey that showed that lower mental ability at age 11 increased the risk of dementia down the track. But what had been less well-defined was whether there were any particular aspects of intelligence in young people that were better predictors (or protectors) of dementia than others. This study goes some way to addressing this. Researchers were able to link sociobehavioural data collected from high school children back in 1960 with Medicare claims data over 50 years later that identified those people who had been diagnosed with Alzheimer's disease and related disorders. Interestingly, poor adolescent performance in other areas of intelligence such as mathematics and visualisation were also associated with dementia but not nearly to the extent of mechanical reasoning and word memory. So why is this so? The study authors say there are a few possible explanations. Maybe the poor performance in adolescence reflected poor brain development earlier in life, a risk factor for dementia. Or maybe these adolescents are more susceptible to neuropathology as they get older? Or maybe they are the adolescents who adopt poor health behaviours such as smoking and little exercise? “Regardless of mechanism, our findings emphasise that early-life risk stretches across the life course,” they said. And what can be done about it? That’s the million-dollar question. The researchers say the hope is if we know the at-risk group we can get aggressive with preventive management early. “Efforts to promote cognitive reserve-building experiences and positive health behaviours throughout the life course may prevent or delay clinical symptoms of Alzheimer's disease and related disorder.” An accompanying editorial takes this concept a little further. Dr Tom Russ, a Scottish psychiatrist says interventional research has identified a number of factors that can potentially influence cognitive reserve. These include modifiable health factors, education, social support, positive affect, stimulating activities and/or novel experiences, and cognitive training. As Dr Russ says, you can’t necessarily change all of these risk factors, and even the ones you can change may become less modifiable later in life. But as this study demonstrates, you may be able to work on a person’s cognitive reserve at different stages throughout their life to ultimately lower their risk of dementia.   Reference
  1. Huang AR, Strombotne KL, Horner EM, Lapham SJ, Adolescent Cognitive Aptitudes and Later-in-Life Alzheimer Disease and Related Disorders. JAMA Network Open [Internet]. 2018 Sep; 1(5): e181726. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2701735 doi:10.1001/jamanetworkopen.2018.1726.
  2. Russ TC, Intelligence, Cognitive Reserve, and Dementia: Time for Intervention? JAMA Network Open [Internet]. 2018 Sep; 1(5): e181724. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2701735 doi:10.1001/jamanetworkopen.2018.1724.

By Dr Linda Calabresi
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Sullivan Nicolaides Pathology
  • Clinical Articles

Prenatal Screening for Chromosome Disorders

Prenatal screening for chromosome disorders by maternal serum screening, ultrasound and non-invasive prenatal tests, such as Harmony®, is an established part of reproductive care in Australia. The overall risk of chromosome disorders rises markedly with maternal age, as shown in Figure 1. (There are two exceptions: Monosomy X, also known as Turner syndrome, and microdeletions, such as 22q11.2, occur independently of maternal age). This does not mean that chromosome screening should be restricted to older mothers. Younger mothers have more babies than older mothers, and the overall outcome is that the majority of pregnancies with a serious chromosome disorder occur in mothers under 35 years of age. For this reason, screening for chromosome disorders in pregnancy should be offered to mothers of all ages. The great majority of these chromosome disorders are new abnormalities that have happened for the first time in this pregnancy. They are not inherited disorders, and genetic testing of the parents provides no information about the risk of such an abnormality. This provides another reason for offering screening for chromosome disorders to all mothers, irrespective of family history.  

The frequency of single-gene disorders at birth

Chromosome disorders are not the only type of genetic condition which can affect the developing foetus. Many serious childhood disorders are due to recessive mutations that have been inherited from parents, with the parents being unaffected by these mutations. A parent who is a carrier of a recessive mutation, that is, having one normal and one abnormal copy of a gene, will not be affected by the abnormal gene. Everyone is a carrier for one or more disorders; this is of no immediate consequence and there usually is no family history of the disorder. The situation changes if both parents are carriers of mutations in the same gene located on one of the autosomes (chromosomes 1-22). The chance of their child inheriting the abnormal gene from each parent, and so developing an autosomal recessive disorder, is 25%. The situation is a little different for a woman with a recessive mutation on an X-chromosome: each of her sons is at 50% risk of inheriting the abnormal gene and being affected, and half of her daughters will be carriers. Overall, the risk of a woman who is an X-linked carrier having an affected child is approximately 25%. There are hundreds of inherited autosomal and X-linked recessive disorders that present in infancy and early childhood. These disorders are individually rare but, together, they are more common than the chromosome disorders for which prenatal screening is widely available and accepted. Further, the risk of these recessive disorders does not vary with maternal age (Figure 1). For mothers under 35 years of age, the risk of having a child with a serious childhood-onset recessive disorder is greater than the risk of having a child with a chromosome disorder.  

Screening potential parents for recessive disorders

These disorders are inherited but there is usually no family history to provide a clue. Until recently, the only way of identifying a carrier of a rare recessive disorder was to diagnose the disorder in their affected child. This has now changed. It is possible to screen a couple for mutations in autosomal genes, and a woman for mutations in X-linked genes, to determine whether they are at 25% risk of having an affected child. This screening test is called ’reproductive carrier screening’. From both a technical and clinical perspective, the challenge lies in choosing which genes to analyse. A number of providers, including Sonic Genetics, offer reproductive carrier screening for mutations responsible for three common disorders: cystic fibrosis and spinal muscular atrophy (both autosomal recessive) and Fragile X syndrome (X-linked recessive). Approximately 6% of people are carriers of one or more of these conditions, and 0.6% (one in 160) couples are at 25% risk of having an affected child. Those couples who are identified as carriers can consider a variety of options, including IVF with a donor gamete, pre-implantation genetic diagnosis, prenatal diagnosis by CVS, or they may make an informed decision to accept the risk. RANZCOG recommends that couples be offered such screening. The cost of this three-gene panel is approximately $400* per person. There is no Medicare rebate for carrier screening; there are exceptions (and restrictions) for people with a documented family history of cystic fibrosis or Fragile X syndrome.  

Expanded reproductive screening

If we were to screen more genes, we would identify more carriers. Sonic Genetics offers a screen of over 300 genes (autosomal and X-linked) which cause serious recessive childhood disorders. We estimate that approximately 70% of Australians are carriers for one or more conditions included in this screen and 3% (one in 30) couples are at 25% risk of having an affected child. This amounts to five times more information than is provided by the three-gene panel. This screen, the Beacon Expanded Carrier Screen, currently costs $995* per person or $1,750* for couples tested together. It is tempting to think that ‘more genes tested = more information for a couple’. This is not the case because the information provided by a carrier screen is also determined by the carrier frequency, mode of inheritance and detection rate of the assay for each gene. Some currently available screens of more than 100 genes provide less information than the three-gene screen described earlier.  

Implementing reproductive screening

Before offering reproductive carrier screening to your patients, it is important to consider some of the nuances, particularly in relation to the Fragile X syndrome (some carriers will develop premature ovarian failure or a tremor/ataxia syndrome in later life) and when there is a family history of a recessive disorder (seek expert advice; do not rely on screening). It is also important to recognise that some couples will not want this carrier information – and others will demand it. Each person needs to be free to make their own decision about what information they wish to have. We provide information about the three-gene and Beacon screens for both requestors and patients on our website. Sonic Genetics also offers genetic counselling free-of-charge for couples who are identified by either of these reproductive carrier screens as being at high risk of having an affected child (see www.sonicgenetics.com.au/rcs/gc).  

Conclusion

It is accepted practice that every woman is offered screening for chromosome disorders in pregnancy, irrespective of age and family history. In a similar vein, every couple should be offered reproductive carrier screening for recessive disorders, irrespective of age and family history. For women under 35 years, the risk of their child having a recessive disorder is greater than the risk of a chromosome disorder. Offering reproductive carrier screening simply represents good medical practice.  

References

RANZCOG. Prenatal screening and diagnostic testing for fetal chromosomal and genetic conditions. 2018 Aug. 35 p. Available from: https://www.ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27s%20Health/Statement%20and%20guidelines/Clinical-Obstetrics/Prenatal-screening.pdf?ext=.pdf Archibald AD, Smith MJ, Burgess T, Scarff KL, Elliott J, Hunt CE, et al. Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests. Genet Med. 2018; 20(5): 513-523 Available from https://www.ncbi.nlm.nih.gov/pubmed/29261177 doi:10.1038/gim.2017.134. Sonic Genetics [Internet]. c2015. Reproductive Carrier Screening; 2018. Available from: www.sonicgenetics.com.au/rcs   General Practice Pathology is a new regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.
By Sullivan Nicolaides Pathology
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Dr Linda Calabresi
  • Clinical Articles

Are We Missing Chronic Pancreatitis? Does it Matter?

The answer to both these questions is yes according to Dr Darren Pavey, gastroenterologist and senior lecturer at the University of NSW. Speaking at the Healthed General Practice Education seminar in Sydney recently, Dr Pavey said there was good international research suggesting that many cases of chronic pancreatitis were going undiagnosed and the condition was far more prevalent than previously recognised. Overseas studies including cohorts of randomly selected adult patients suggest a prevalence of between 6-12%, with the condition being more likely among patients with recent onset type 2 diabetes, excess alcohol intake, smokers and those over 40 years of age, he said. And in response to the question of whether it is important to diagnose this condition, Dr Pavey said chronic pancreatitis not only caused immediate symptoms usually including pain, diarrhoea and weight loss but commonly had longer-term consequences such as pancreatic exocrine insufficiency (where there is less than 10% pancreatic function) and an increased risk of diabetes, malnutrition and even pancreatic cancer. Certainly, an incentive to diagnose and treat earlier rather than later. Part of the challenge in recognising the condition is that the classic triad of symptoms, namely abdominal pain, diarrhoea and weight loss are common to a variety of medical conditions including IBD and IBS. What’s more, abdominal pain, which many doctors would have thought had to be present with pancreatitis does not always occur in chronic pancreatitis especially when it is idiopathic which is the more common variety of chronic pancreatitis. In fact, pain is only present in about half the cases of idiopathic chronic pancreatitis. Idiopathic pancreatitis constitute 55% of all cases, the other 45% being alcohol-related. Abdominal pain tends to be a more consistent feature of alcoholic chronic pancreatitis. So if you have a patient in the right age group (about 40 to 60 years), who has chronic diarrhoea, weight loss and maybe abdominal pain and you suspect they might have chronic pancreatitis what do you do? The most common screening test for chronic pancreatitis is now a faecal elastase-1 stool test, requiring a single formed stool sample, said Dr Pavey. The test has a high specificity and sensitivity (both over 90%) and is readily available to Australian GPs, although it does not attract a Medicare rebate and costs approximately $60. The test is positive if the concentration of faecal elastase is less than 200mcg/g. In terms of imaging, CT is usually the option of first choice with signs of calcification and atrophy being pathognomonic of significant chronic pancreatitis. Aside from the need to stop drinking and smoking, treatment revolves around replacement of the pancreatic enzymes, which is available as a capsule taken orally (Creon). The deficiency of these enzymes is the chief cause of the diarrhoea, malabsorption, and weight loss so replacing them not only alleviates the symptoms but will also help prevent some of significant sequelae associated with this ongoing condition. Interestingly, a study of patients newly diagnosed with pancreatic cancer, showed that 66% had pancreatic exocrine insufficiency at diagnosis, and after two months this prevalence grew to 93% Dr Pavey advises starting patients with known chronic pancreatitis on 25,000 lipase units (Creon) with every meal and 10,000 units with every snack, and recommends patients eat six smaller meals during the day rather than three larger meals. This replacement therapy would then be titrated up to 40,000 units with a meal and 25,000 units for a snack. For those whose need was greater, replacement could even be increased to 80,000 units per meal. There was no need to put patients on a reduced fat diet when they were on pancreatic enzyme replacement therapy however they often had a highly acidic upper gastrointestinal environment and required acid suppression treatment. In conclusion, Dr Pavey advises clinicians to have a high index of suspicion for this poorly-recognised but important condition. “[Doctors] should be aware of the problem of underdiagnosing this condition and have a low threshold for checking faecal elastase and assessing pancreatic insufficiency,” he said.

By Dr Linda Calabresi
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Loubaba Mamluk
  • Clinical Articles

Health Risks of Light Drinking in Pregnancy Confirms that Abstention is the Safest Approach

While heavy drinking is clearly harmful to the unborn baby, often leading to miscarriage, premature birth and foetal alcohol syndrome, the possible effects of light drinking have been less clear. High quality data on this issue is lacking due to ethical and methodological issues. On the one hand, experiments (clinical trials) in this area are impossible to conduct. Clinical trials would include randomising a group of pregnant women to drinking alcohol, which is clearly unethical. On the other hand, in observational studies we can never be sure whether the results are due to alcohol or other factors, such as wealth or education.

‘One glass is OK, isn’t it?’

Women often ask about “safe” levels of drinking during pregnancy. The distinction between light drinking and abstinence is indeed the point of most tension and confusion for health professionals and pregnant women, and public health guidance varies worldwide. Our new review of the evidence, published in BMJ Open, shows that this specific question is not being researched thoroughly enough. As there can be no clinical trial research carried out on this topic, we systematically reviewed all the data from a wide range of high quality observational studies. These studies involved pregnant women, or women trying to conceive, who reported on their alcohol use before the baby was born. The researchers assessed the impact of light drinking, compared with no alcohol at all.   >> Read More Source: The Conversation
By Loubaba Mamluk, Luisa Zuccolo
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Dr Linda Calabresi
  • Clinical Articles

Bowel Cancer Screening: Who, When, How?

New NHMRC guidelines put age and family history up front and centre in determining who should be screened for bowel cancer with colonoscopy and who needs iFOBT. It has been known for some time that family history can influence the risk of developing bowel cancer, Australia’s second most common cause of cancer death. But it is also known that specific, identified genetic mutations causing conditions such as Lynch syndrome or familial adenomatous polyposis are rare, accounting for less than 5% of all bowel cancers diagnosed. At most, the researchers say, this only explains half of the reasons why family history is a risk factor for bowel cancer. “The remainder of the observed increases in familial risk could be due in part to mutations in yet to be discovered colorectal cancer susceptibility genes, polygenic factors such as single-nucleotide polymorphisms, or dietary and other lifestyle factors shared by family members,” the guideline authors said in the Medical Journal of Australia. Therefore, the researchers, led by Professor Mark Jenkins, director of the Centre for Epidemiology and Biostatistics, in the University of Melbourne’s School of Population and Global Health, analysed all the available cohort studies to determine the risk of developing colorectal cancer based on age and family history. They categorised cohorts into one of three levels of risk and this determined at what age screening would be worthwhile starting and which screening method was most appropriate. The screening guidelines exclude people with a known or suspected cancer-causing genetic syndrome, as these people require much more intensive screening and should be managed in a family cancer clinic. The majority of Australians (90%) fall into the lowest risk category, category 1, which puts their risk at age 40 of developing colorectal cancer in the next 10 years at about 0.25% (one in 400). As with most other cancers age is a risk factor, so it is unsurprising that at age 50 the risk of developing this cancer has risen to 0.9%. Screening for this category 1 group should be the two-yearly iFOBT test that is currently available via the National Bowel Screening program for adults between the ages of 50 and 74 years. Interestingly, people aged 75 and older still develop bowel cancer but there have been no studies to determine the cost-effectiveness or benefit vs risk analysis of screening in this age group which is why the program and the guideline recommendations stop at 74 years. One of the differences in these new guidelines, a revision from the previous ones published back in 2005, is that people with a first degree relative who has had or has a bowel cancer at age 55 or older are still considered at average risk (category 1). However, people with this history might consider starting the iFOBT screening at a younger age (45 years), the guideline authors suggest. Category 2 includes people with a moderately increased risk of developing colorectal cancer, 3-6 times higher than average. This will mean having a first degree relative diagnosed with a bowel cancer before the age of 55 or having two first degree relatives who developed bowel cancer at any age (or one first degree and two second degree relatives). Category 2 people are recommended to have iFOBT every two years for the decade between ages 40 and 50 and then switch to five yearly colonoscopies until the age of 75. Finally, the high risk, category 3 is for all those patients without a genetic syndrome whose family history is even stronger than those people in category 2. Their risk is between 7-10 times higher than average. This includes people with at least three first-degree relatives who have been diagnosed with colorectal cancer at any age or people who have multiple relatives with the cancer including at least one diagnosed before aged 55. These high-risk people need to start screening earlier, with the guidelines recommending iFOBT every two years starting at age 35 and continuing for 10 years and then having a colonoscopy every five years between the ages of 45 and 75. Of note is that the revised guidelines have deleted the reference in the previous guidelines to starting screening 10 years before the earliest age colorectal cancer was diagnosed in a first degree relative. “There have been no studies conducted to determine the utility of beginning screening 10 years before the earliest diagnosis in the family, which was a recommendation in the 2005 guidelines and, therefore, it is not included in these guidelines,” they said. The new guidelines aim not only to more strongly define risk based on the latest evidence, but also to determine the most appropriate screening method based on that risk, taking into consideration cost-effectiveness and rationalisation of available services, in particular, colonoscopies.   Reference Jenkins MA, Ouakrim DA, Boussioutas A, Hopper JL, Ee HC, Emery JD, et al. Revised Australian national guidelines for colorectal cancer screening: family history. Med J Aust. 2018 Oct 29. doi: 10.5694/mja18.00142. [epub ahead of print]

By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

Intellectual Disability More Likely with Some ART

Australian research has found an increased risk of intellectual disability with some forms of Assisted Reproductive Technology (ART). The WA study published in Pediatrics found that one in 48 children conceived using ART were diagnosed with an intellectual disability, compared with only one in 59 children conceived naturally. And the risk was even greater for certain subgroups within the ART cohort. “The risk was more than doubled for those born very preterm, for severe [intellectual disability] and after intracytoplasmic sperm injection (ICSI) treatments,” said the researchers from the Telethon Kids Institute. To conduct the study, researchers analysed population registers of over 200,000 live births occurring between 1994 and 2002 in Western Australia and examined data on ART and diagnoses of intellectual disability occurring within eight years of follow-up. The fact that the study findings were based on analyses of statistics from almost 20 years ago was acknowledged by the authors, especially since ART practices have changed greatly since then. “Our study included children born from 1994 to 2002 when multiple embryo transfer was common practice in Western Australia,” they said. This increased the likelihood of a multiple pregnancy and preterm birth. However even when the analyses are restricted to singleton births the small increased risk of intellectual disability persisted but was not as great. The link between ICSI-conceived children and intellectual disability was also of interest. At the time, this technique was restricted to couples with severe male-factor subfertility and was often associated with older aged males. “Genetic abnormalities occur more frequently in men who are infertile, so ICSI (which bypasses natural selection barriers) may allow for the transmission of chromosomal anomalies in the offspring,” the authors said. According to the study, one in 32 children conceived using ICSI were diagnosed with an intellectual disability. ICSI is now used more broadly, prompting concerns. As lead author, Dr Michele Hansen said, “[ICSI] is currently used in 63 per cent of treatment cycles.” “Our findings show an urgent need for more recent data to establish whether the increased risks of intellectual disability seen in children conceived using ICSI are solely related to severe male subfertility and older paternal age, or if there are other risks associated with the technique itself.” Overall the study findings provide supportive evidence for Australia’s current IVF policy of single embryo transfer unlike many other countries where multiple embryo transfers are still routinely performed. The researchers also point out the study has implications for the use of ICSI, or more exactly restricting the use of ICSI and recognising the increased risk of genetic anomalies that might occur in children conceived in this way. “These couples may opt to use preimplantation genetic testing to maximise the transfer of chromosomally normal embryos,” they suggest.  

Reference

Hansen M, Greenop KR, Bourke J, Baynam G, Hart RJ, Leonard H. Intellectual Disability in Children Conceived Using Assisted Reproductive Technology. Pediatrics. 2018; 142(6): e20181269. DOI 10.1542/peds.2018-1269
By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

Body Fat more Important than BMI in Breast Cancer

Women with a normal BMI can no longer tick off weight as breast cancer risk factor, US researchers say. According to their study, published in JAMA Oncology, it’s body fat that increases the risk even if the woman falls into a healthy weight range. The study was in fact a secondary analysis of the Women’s Health Initiative clinical trial along with observational study cohorts involving almost 3500 post-menopausal, healthy BMI women who at baseline had their body fat analysed (by DXA) and were then followed up for a median duration of 16 years. What the researchers discovered was that women in the highest quartile for total body fat and trunk fat mass were about twice as likely to develop ER-positive breast cancer. “In this long-term prospective study of postmenopausal with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancers,” the study authors spelled. Perhaps less surprisingly, the analysis also found that the breast cancer risk increased incrementally as the body fat levels increased. “We found a 56% increase in the risk of developing ER-positive breast cancer per 5-kg increase in trunk fat, despite a normal BMI,” they said. The proposed mechanism that explains why high body fat levels increases the risk of breast cancer, is much the same as the known mechanism that explains the link between obesity and breast cancer risk. People with high body fat levels tend to have adipocyte hypertrophy and cell death which means the adipose tissue is chronically although sub-clinically inflamed. This inflammation triggers the production of a number of factors including an increased ratio of oestrogens to androgens which is believed to predispose to the development of oestrogen-dependent breast cancer. Basically the study authors believe these women with high body fat but normal BMI, are ‘metabolically obese’ even though they do not fit the standard definition of obese. And while using DXA to determine body fat levels is highly accurate, such an assessment is rarely used in everyday practice. Most doctors look only at BMI measurements or they may also assess waist measurement which has variable sensitivity in terms of diagnosing excess body fat. Consequently, the researchers say, many non-overweight women who are at increased risk of breast cancer because of their high adiposity may be going unrecognised. So where does that leave us? Here the study authors were less definitive. The link between body fat and breast cancer is clear but, they say, more research is needed to determine the most appropriate management for this cohort of women with high body fat levels and normal BMI. “Future studies are needed to determine whether interventions that reduce fat mass, such as diet and exercise programs or medications including aromatase inhibitors, might lower the elevated risk of breast cancer in this population with normal BMI,” they concluded.

Reference

Iyengar NM, Arthur R, Manson JE, Chlebowski RT, Kroenke CH, Peterson L, et al. Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index: A Secondary Analysis of a Randomized Clinical Trial and Observational Study. JAMA 2018 Dec 6. DOI: [10.1001/jamaoncol.2018.5327] [Epub ahead of print]
By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

Preventing Alzheimer Disease

At first read, the study results seemed disappointing. Yet another promising premise fails to deliver when it comes to actual proof. But the researchers aren’t ready to give up on this hypothesis just yet. In fact, commentators on the study say the results offer ‘great hope’ and represent ‘a major leap forward.’ The SPRINT MIND study, recently published in JAMA was investigating whether intensive blood pressure control (to a systolic less than 120mmHg) worked better than standard blood pressure control (SBP<140mmHg) at reducing the risk of mild cognitive impairment and dementia. This randomised controlled trial was a component of the well-publicised Systolic Blood Pressure Intervention Trial (SPRINT) which looked at the effect of more intensive blood pressure control on cardiovascular and renal outcomes in addition to cognitive function in over 9000 people without a history of diabetes or stroke. Basically, what this study showed was that intensive blood pressure control to a target of less than 120mmHg did not reduce the incidence of probable dementia compared to lowering BP to a target of less than 140mmHg. Depressing, yes? No, say the study authors. Firstly, they say the study demonstrated no ill-effects of intensive BP lowering – which has been an issue of concern for some who have been worried that lowering the BP could decrease cerebral perfusion thereby harming cognitive function. In fact, the study authors showed quite the opposite was true. The intervention actually helped protect cognitive ability. “This is the first trial, to our knowledge, to demonstrate an intervention that significantly reduces the occurrence of [mild cognitive impairment], a well-established risk factor for dementia, as well as the combined occurrence of [mild cognitive impairment] or dementia,” they said. The study authors suggest the lack of benefit in dementia may be due to the fact the SPRINT study was terminated early following the demonstration of benefit of intensive BP control on cardiovascular outcomes and all-cause mortality. Because of this shortened time frame and the fact that there were fewer than expected cases of dementia, they suggest the study may have been ‘underpowered’ to show a result for lowering the risk of dementia. They also say there were fewer cases of dementia among the intensive treatment group compared with the standard treatment group (7.2 vs 8.6 cases per 1000 patient years) even though this wasn’t statistically significant. We cannot know whether this trend would have reached statistical significance had the intervention continued. An accompanying editorial views the study and the results with a good deal of positivity. “For older adults, almost all of who have concern about being diagnosed with Alzheimer Disease and related dementia, [this study] offers great hope,” the US epidemiologist, Dr Kristine Yaffe, said. She points out that this a readily modifiable risk factor, and we should be accelerating our efforts into investigating whether this, along with other vascular health interventions such as physical activity, can indeed prevent dementia, building on the positive results of this study. “The SPRINT MIND study may not be the final approach for prevention of Alzheimer disease or other cognitive impairment but it represents a major leap forward in what has emerged as a marathon journey.”

Reference

Yaffe, K. Prevention of Cognitive Impairment With Intensive Systolic Blood Pressure Control. JAMA [Internet]. 2019 Jan 28. DOI: 10.1001/jama.2019.0008 [Epub ahead of print]
By Dr Linda Calabresi
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Sullivan Nicolaides Pathology
  • Clinical Articles

Guide to Allergy Testing

Allergic disorders result from an inappropriate, usually IgE-mediated, immune response upon exposure to either environmental or food allergens. Common manifestations of allergy include rhinoconjunctivitis, asthma, eczema, acute urticaria and anaphylaxis. Disorders, such as chronic urticaria, hereditary angioedema and T-cell contact dermatitis (metal allergy), while clinically similar in some ways, are not IgE-mediated. Allergic disease manifests in different ways through life and the likely causative agents can also change with age (see Table 1).

Tests used in the diagnosis of IgE-mediated allergy

Total IgE Higher levels of total IgE are often found in patients with allergic conditions. However, normal total IgE does not exclude allergy. Total IgE is also elevated in other conditions including parasitic infections and allergic bronchopulmonary aspergillosis. It is used increasingly in determining anti-IgE therapy in moderate to severe asthmatics. Allergen-specific IgE Allergen-specific IgE can be detected for a large variety of allergens. The presence of a specific IgE to allergen can suggest allergic disease and is detected via a blood test (RAST or radioallergosorbent test) or skin prick test. RAST tests detect many of the different proteins within an individual allergen. Recombinant allergen testing Of the many proteins within a substance, only a few may cause allergic symptoms. Recombinant allergen testing looks for specific characterised protein within an allergen. Interpretation of RAST tests The presence of detectable specific IgE to an allergen does not confirm the patient is allergic to that substance. All results must be interpreted in conjunction with the clinical history of the patient. Low levels of detectable specific IgE can confirm the presence of allergy in the right clinical context. RAST testing aids in the assessment of, and identification of allergic sensitisation, but is not to be used alone as the deciding factor for inclusion or exclusion of allergy. As the level of specific IgE increases, the likelihood of clinical relevance also increases. As shown in Table 2, different allergens have different specific IgE level cutoffs at which serious allergy is >95% likely (positive predictive value or PPV). The range of values is vastly different between allergens and is affected by age and also by geographic region. Table 2 defines levels at which exposure, or a challenge, would be highly hazardous for a patient. Importantly, many patients could have serious reactions at much lower levels.   [table id=1 /]   [table id=2 /]

RAST tests

RAST tests are available for a range of allergens, however Medicare criteria limits rebates based on the number, type and frequency of tests. Medicare Australia limits rebates for RAST tests to a maximum of four specific allergens and/or mixes per pathology request and a maximum of four RAST test episodes per year. When ordering RAST tests, it is advisable to include allergens the patient feels are relevant and those likely for the clinical scenario. For common clinical scenarios we recommend the following: Childhood eczema Age <2 years: Milk, Egg, Wheat, Peanut Age >2 years: Milk, Egg, Peanut, Dust mite Additional allergens or an extended RAST combined allergy panel may be ordered. Asthma and allergic rhinoconjunctivitis Dust mite, Grass mix, Animal dander Additional allergens may be ordered or substituted if relevant (e.g. cat dander instead of animal dander). An extended RAST inhalant panel is also available. Default panel if no allergens are specified and no clinical notes are provided Age <5 years: Dust mite, Grass mix, Food Mix Age >5 years: Dust mite, Grass mix, Animal Mix Anaphylaxis Anaphylaxis is a severe life-threatening allergic reaction. It is recommended these patients require specialist assessment by a clinical immunologist or allergist. Initial testing should look for the causative allergen if possible. It is important to note that a negative RAST test does not exclude the allergen tested. RAST testing recommendations ­
  • Test individual likely causative allergen i.e. food, stinging insect. ­
  • Tryptase, if done within 2-6 hours of reaction, can support the occurrence of an allergic reaction. ­
  • Useful as an assessment of mastocytosis (condition with increased numbers of mast cells)

Extended RAST panels

Extended RAST panels have been developed to represent the common allergens encountered clinically in practice. They are particularly relevant in our geographic region and replace the skin prick test panel which is no longer available. Additional allergens may also be requested. All results must be interpreted in conjunction with the patient’s clinical history. Extended RAST Food Panel ­
  • Covers common food-related allergens
  • Almond; Hazelnut; Sesame seed; Banana; Mango; Shrimp (prawn); Cashew; Milk (cow); Soybean; Codfish; Peanut; Walnut; Egg white; Rice; Wheat
Extended RAST Nut Allergy Panel ­
  • Broad collection of commonly consumed nuts, including peanuts ­
  • Individual nut testing with appropriate clinical history is preferred ­
  • Recommend to discuss results with a clinical immunologist or allergist
  • Almond; Macadamia; Pine nut; Brazil; Peanut; Sesame seed; Cashew; Peanut (Ara-h2); Walnut; Hazelnut; Pecan
Extended RAST Combined Allergy Panel ­
  • Combination of common food and environmental allergens ­
  • Replaces the skin prick test panel (no longer available)
  • Almond; Dust mite; Mould mix; Cashew nut; Egg white; Peanut; Cat dander; Grass mix; Shrimp (prawn); Codfish; Hazelnut; Soy; Dog dander; Milk (cow); Wheat
  • * Preferable for children (<12 years) due to low serum volume
Extended RAST Inhalant Panel ­
  • Covers common environmental allergens ­
  • Useful for asthma and allergic rhinitis
  • Acacia (wattle); Blomia tropicalis; Dust mite; Alternaria alternate; Cat dander; Eucalyptus; Aspergillus fumigatus; Cladosporium; Horse dander; Bahia grass; Common ragweed; Johnson grass; Bermuda grass; Dog dander; Perennial rye grass

Recombinant allergens

Omega-5 gliadin ­
  • A component of wheat ­
  • Associated with anaphylaxis ­
  • Often in the context of eating wheat and physical activity within 1-2 hours
Alpha-gal (mammalian meat allergy) ­
  • Associated with anaphylaxis; often delayed following consumption of meat (beef, lamb, pork) ­
  • Related to tick bites
Peanut Allergy Risk Assessment ­
  • Peanuts like all food is made up of many different proteins ­
  • Ara-h2 is associated with anaphylaxis to peanut ­
  • Can assist with risk assessment and should be done in conjunction with a clinical immunologist or allergist ­
  • A negative Ara-h2 in peanut positive patient does not imply there is no risk to anaphylaxis
  • Results of RAST tests can also be of use in monitoring ongoing allergy in patients in conjunction with their treating clinician

How to order allergy tests

RAST tests - standard panels Medicare Australia limits rebates for RAST tests to a maximum of four specific allergens and/or mixes per pathology request and a maximum of four RAST test episodes per year. Extended RAST tests (Medicare rebate + $120* per panel)
  • Extended RAST Food
  • Extended RAST Nut
  • Extended RAST Combined
  • Extended RAST Inhalant
Please note, extended RAST panels are not bulk billed. Recombinant allergen tests (Medicare rebate + $60* each)
  • Alpha-gal
  • Omega-5 gliadin
  • Peanut (Ara-h2)
  • Peanut Allergy Risk Assessment
  General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.
By Sullivan Nicolaides Pathology
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Dr Linda Calabresi
  • Clinical Articles

Bad News for Sinus Sufferers

Chronic rhinosinusitis is a misery-generating condition – literally. According to a large study just published in The Journal of the American Medical Association, having chronic rhinosinusitis significantly increases your risk of depression and anxiety. And if you also have nasal polyps the risk is higher still. The Korean study was admittedly observational but it did include almost 50,000 individuals from the general population and followed them up for 11 years. Researchers found, over the duration of the study, those people with chronic rhinosinusitis were 54% more likely to develop depression and 57% more likely to develop anxiety than those people who did not suffer this condition. And if nasal polyps accompanied the rhinosinusitis the increase in likelihood for both mental illnesses jumped to the early 60s (61% and 63% respectively). So what are the implications of this study? Well – they are fairly straightforward really. “Physicians should be aware of the potential comorbidities observed in patients with [chronic rhinosinusitis] and provide therapy to reduce the risk of depression and anxiety in these patients,” the study authors helpfully concluded. What we don’t know of course, being simply an observational study without any intervention to test, is whether effectively treating the rhinosinusitis helps the depression or anxiety, and importantly, whether surgically removing the polyps can make a difference to this psychological side-effect. The researchers actually even distance themselves from the conclusion that chronic rhinosinusitis causes depression and anxiety, citing the chicken and egg phenomena. “Whether depression and anxiety amplify the symptoms of [chronic rhinosinusitis] or whether these conditions are the consequence of [chronic rhinosinusitis]is unknown,” they said. But they do say their findings support previous research that has suggested an association between the conditions. They also say their study allowed analysis of the specific phenotype responsible for the chronic rhinosinusitis – whether it be predominantly T1 or T2 response derived. What they found was the association held true regardless of the phenotype – suggesting this was more to do with personality and symptoms than physiology. All in all, what the study authors suggest is that given how common chronic rhinosinusitis is in the population, it is worthwhile keeping a high indexation of suspicion for the development of depression and anxiety not only for the patients’ current quality of life but also because these conditions can affect health outcomes down the line. “[T]hese psychiatric comorbidities may influence not only the diagnosis of [chronic rhinosinusitis] but also its therapeutic and surgical outcomes,” the study authors said.  

Reference:

Kim JY, Ko I, Kim MS, Yu MS, Cho BJ, Kim DK. Association of Chronic Rhinosinusitis With Depression and Anxiety in a Nationwide Insurance Population. JAMA Otolaryngol Head Neck Surg. 2019 Feb 7.  DOI: 10.1001/jamaoto.2018.4103 [Epub ahead of print].
By Dr Linda Calabresi
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Dr Cameron Webb
  • Clinical Articles

Explainer: What is Murray Valley Encephalitis Virus?

Western Australian health authorities recently issued warnings about Murray Valley encephalitis, a serious disease that can spread by the bite of an infected mosquito and cause inflammation of the brain. Thankfully, no human cases have been reported this wet season. The virus that causes the disease was detected in chickens in the Kimberley region. These “sentinel chickens” act as an early warning system for potential disease outbreaks.

What is Murray Valley encephalitis virus?

Murray Valley encephalitis virus is named after the Murray Valley in southeastern Australia. The virus was first isolated from patients who died from encephalitis during an outbreak there in 1951. The virus is a member of the Flavivirus family and is closely related to Japanese encephalitis virus, a major cause of encephalitis in Asia. Murray Valley encephalitis virus is found in northern Australia circulating between mosquitoes, especially Culex annulirostris, and water birds. Occasionally the virus spreads to southern regions, as mosquitoes come into contact with infected birds that have migrated from northern regions.

How serious is the illness?

After being transmitted by an infected mosquito, the virus incubates for around two weeks. Most people infected don’t develop symptoms. But, if you’re unlucky, you could develop symptoms ranging from fever and headache to paralysis, encephalitis and coma. Around 40% of people who develop symptoms won’t fully recover and about 25% die. Generally, one or two human cases are reported in Australia per year. Since the 1950s, there have been sporadic outbreaks of Murray Valley encephalitis, most notably in 1974 and 2011. The 1974 outbreak was Australia-wide, resulting in 58 cases and 12 deaths. It’s likely the virus has been causing disease since at least the early 1900s when epidemics of encephalitis were attributed to a mysterious illness called Australian X disease.

Early warning system

Given the severity of Murray Valley encephalitis, health authorities rely on early warning systems to guide their responses. One of the most valuable surveillance tools to date have been chooks because the virus circulates between birds and mosquitoes. Flocks of chickens are placed in areas with past evidence of virus circulation and where mosquitoes are buzzing about. Chickens are highly susceptible to infection so blood samples are routinely taken and analysed to determine evidence of virus infection. If a chicken tests positive, the virus has been active in an area. The good news is that even if the chickens have been bitten, they don’t get sick. Mosquitoes can also be collected in the field using a variety of traps. Captured mosquitoes are counted, grouped by species and tested to see if they’re carrying the virus. This method is very sensitive: it can identify as little as one infected mosquito in a group of 1,000. But processing is labour-intensive.

How can technology help track the virus?

Novel approaches are allowing scientists to more effectively detect viruses in mosquito populations. Mosquitoes feed on more than just blood. They also need a sugar fix from time to time, usually plant nectar. When they feed on sugary substances, they eject small amounts of virus in their saliva. This led researchers to develop traps that contain special cards coated in honey. When the mosquitoes feed on the cards, they spit out virus, which specific tests can then detect. We are also investigating whether mosquito poo could be used to enhance the sugar-based surveillance system. Mosquitoes spit only tiny amounts of virus, whereas they poo a lot (300 times more than they spit). This mosquito poo can contain a treasure trove of genetic material, including viruses. But we’re still working out the best way to collect the poo.

Staying safe from Murray Valley encephalitis

There is no vaccine or specific treatment for the virus. Avoiding mosquito bites is the only way to protect yourself from the virus. You can do this by:
  • wearing protective clothing when outdoors
  • avoiding being outdoors when the mosquitoes that transmit the virus are most active (dawn and dusk)
  • using repellents, mosquito coils, insect screens and mosquito nets
  • following public health advisories for your area.
The virus is very rare and your chances of contracting the disease are extremely low, but not being bitten is the best defence.The Conversation

- Ana Ramírez, PhD candidate, James Cook University; Andrew Francis van den Hurk, Medical Entomologist, The University of Queensland; Cameron Webb, Clinical Lecturer and Principal Hospital Scientist, University of Sydney, and Scott Ritchie, Professorial Research Fellow, James Cook University

This article is republished from The Conversation under a Creative Commons license. Read the original article.
By Dr Cameron Webb, Ana Ramírez, Andrew Francis van den Hurk, Scott Ritchie, Dr Nicholas J Clark
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Myriam Gharbi, Joseph H Drysdale, Hannah Lishman, Rosalind Goudie, Mariam Molokhia, Alan P Johnson, Alison H Holmes, Paul Aylin & Alastair D Hay
  • Clinical Articles

Don’t Delay Antibiotics for UTI

So here’s the exception that proves the rule. Urinary tract infections need immediate treatment with antibiotics to avoid an increased risk of sepsis and death. That’s the quite definitive conclusion from a large retrospective study involving GP data from the UK recently published in the BMJ. After analysing the records of over 150,000 patients, aged 65 and over presenting to their GP with a suspected or confirmed UTI, the researchers found those whose antibiotic treatment was delayed or deferred were up to eight times more likely to develop sepsis in the following 60 days compared to the group who were given antibiotics from the beginning. And those patients who were not given antibiotics at all, they were twice as likely to die as their medicated counterparts. Most of the infections were caused by Escherichia Coli, and trimethoprim or nitrofurantoin were the most common antibiotics prescribed. As the study showed, sepsis is not a common sequela of UTI, occurring in just .5% of cases. But the fact remains if antibiotics were delayed or withheld altogether the incidence jumped to 2.2% and 2.9% respectively which is significant and totally unnecessary. Understandably outcomes were worse the older the patient, and men had more adverse outcomes than women, but even accounting for multiple variable factors the basic conclusion remained the same. “Our study suggests the early initiation of antibiotics for UTI in older high-risk adult populations (especially men aged >85 years) should be recommended to prevent serious complications”, the study authors said. Of concern to the researchers was the relatively large number of older patients (about 7%) who were diagnosed with a UTI but not treated. They suggest antimicrobial stewardship programmes encouraging more judicious use of antibiotics may be at least, in part, to blame. That, and the risk of elderly patients developing Clostridium difficile infection following antibiotic use. But while ‘delayed or deferred’ antibiotic treatment was not generally associated with serious adverse outcomes for some self-limiting illnesses such as upper respiratory tract infections, this study suggests it is not a good idea for UTIs. “In our study, deferred antibiotics were associated with less severe adverse outcomes than no antibiotics for older adults but still showed a significantly higher risk of mortality compared with immediate antibiotics,” the researchers said. An accompanying editorial by a UK GP academic says the study highlights one of the many dilemmas that occur in general practice. “[GPs face] the daily challenge of ensuring that patients who are unlikely to benefit are not treated, whereas those who require antibiotics receive the right class, at the right time, at the right dose, and for the right duration,” he wrote. And while agreeing with the study authors concluding advice, that all older patients with suspected UTI should be treated from day one he does suggest further research is needed. Research could help determine the most appropriate antibiotic in this situation, and if there are any particular groups in this 65 and over cohort who it would be safe to leave off antibiotic treatment until the result of the culture and sensitivities are known. - Myriam Gharbi, NIHR Health Protection Research Unit, Imperial College London; Joseph H Drysdale, Department of Primary Care and Public Health, Imperial College London; Hannah Lishman, Medical School, St George's University of London UK; Rosalind Goudie, Nuffield Department of Population Health, University of Oxford, UK; Mariam Molokhia, Department of Primary Care and Public Health Sciences, King's College, London, UK; Alan P Johnson, Healthcare-Associated Infections and Antimicrobial Resistance Division, London, UK; Alison H Holmes, NIHR Health Protection Research Unit, Imperial College London; Paul Aylin, NIHR Health Protection Research Unit, Imperial College London This article is referenced from THEBMJ. Read the original article. - Alastair D Hay, Centre for Academic Primary Care, Bristol Medical School: Population Health Sciences, University of Bristol, Canynge Hall, Bristol, UK This article is referenced from THEBMJ. Read the original article.

By Myriam Gharbi, Joseph H Drysdale, Hannah Lishman, Rosalind Goudie, Mariam Molokhia, Alan P Johnson, Alison H Holmes, Paul Aylin & Alastair D Hay

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