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Oncology

Clinical Articles

Increasing The Accuracy Of Melanoma Diagnosis

The diagnosis of pigmented skin lesions is amongst the most challenging and potentially dangerous areas of skin cancer medicine and dermatopathology. In this article, we discuss the limitations of histopathological diagnosis, and point to ways that the clinician may be able to assist the pathologist to minimise adverse outcomes.

Reliability of pathological diagnosis

To a large extent, the pathological diagnosis of melanocytic lesions is subjective. Most lesions can be readily and reliably diagnosed by an experienced pathologist, but some lesions may possess morphological features that are not stereotypical. In such cases, different observers may render different diagnoses and, in a small number of cases, the diagnoses may range between benignity, on the one hand, and malignancy on the other. The extent of agreement between observers (or for a single observer making a number of observations) can be measured using a statistical tool called a kappa coefficient, where κ = 1 is perfect agreement, κ = −1 is perfect disagreement and κ = 0 is chance agreement. A number of studies have examined the reliability of pathologists in reporting pigmented skin lesions. Although almost all of these studies tend to be distorted because of case selection (with most papers studying ‘difficult cases’), the results are worth noting. In distinguishing melanoma from benign lesions, kappa coefficients around 0.5 (‘moderate agreement’) are reported. In one study, where cases were not selected, a kappa coefficient of 0.6 was achieved and, in more concrete terms, this meant that in 25% of cases, at least one of the four dermatopathologists in the study disagreed with the diagnosis of the remainder. Other studies have a narrower focus. In dividing naevi into dysplastic, banal or intermediate categories, κ = 0.34 (‘fair agreement’), and in grading dysplasia, κ = 0.2–0.4 (‘slight to fair agreement’). These disappointing results mean that, in practice, expert dermatopathologists agree on the degree of dysplasia in less than 50% of cases. Difficulties also arise in the diagnosis of ‘Spitzoid’ lesions. This rubric encompasses Spitz naevi, so-called ‘atypical Spitz naevi’ and melanomas with morphological features similar to those seen in Spitz naevi. In one study, world expert dermatopathologists were unable to agree on cases of Spitz naevi, except in one case. Unfortunately, this case ultimately proved to be a fatal melanoma. Other areas of poor diagnostic concordance relate to the diagnosis of melanoma in childhood, and in the diagnosis of cellular blue naevus.

The clinician’s role in assisting the pathologist

The problems which might arise from the inability of even expert pathologists to render reliable diagnoses in a subset of cases can be ameliorated by an insightful and prudent clinician. The surgeon must provide adequate clinical information and an adequate specimen. The importance of clinical information cannot be overstated. Professor Peter Soyer, from the University of Queensland, and colleagues, showed that incremental increases in submitted clinical information improved the concordance of diagnoses rendered by a group of expert dermatopathologists. Moreover, the pathologists reported a substantial increase in the level of confidence in the diagnosis. Unfortunately, it remains the case that, in Australia and New Zealand, useful clinical information is not provided in around one third of specimen submissions. In addition to the site and demographic details, the most pertinent information includes the clinical history, the size of the lesion and the clinical index of suspicion. Increasingly, more experienced clinicians provide dermatoscopic descriptions and photographs, and this additional information can be invaluable. Biopsy technique has a major impact in the reliability of dermatopathological diagnoses. As a general rule, any lesion suspected of being a melanoma, and where the major differential diagnosis is a naevus, should be excised. This is the case because the features which permit clinical diagnosis of melanoma have microscopic correlates which the pathologist uses to establish the diagnosis. In particular, the symmetry of the lesion, the circumscription of its borders and the regularity in which the melanocytes are disposed, all require substantial breadth in a specimen for assessment. Pathologists recognise that, on occasion, excisional biopsy is not feasible, but clinicians must be mindful that in parte biopsy specimens are associated with a very substantial increase in false negative and false positive diagnoses, and that interpretation of the pathology report should be tempered with this knowledge. In a recent study from Melbourne, shave biopsies were associated with a 2.5 times risk of misdiagnosis, compared with excisional biopsies, and punch biopsies, 17 times. False negative diagnoses with an adverse outcome were 20 times more likely with (partial) punch biopsies. It follows that the use of partial punch biopsies for diagnosis of melanocytic lesions is potentially dangerous, and this technique is inappropriate in most instances. Examples where their use might be appropriate are the biopsy of a papule to distinguish a dermal naevus from a small nodular basal cell carcinoma, and the biopsy of an irregular pigmented macule on the face, where the diagnosis is either a solar lentigo or melanoma. In both of these examples, the diagnosis can be made by identifying the cellular constituents of the lesion, that is, there is no requirement accurately to assess the architecture. The expert clinician cannot be a passive recipient of a pathology report. Often, reports will have diagnoses couched in terms like ‘suggestive of’, ‘features favouring’ or similar phrases, which reflect the pathologist’s lack of certainty in the diagnosis. In such circumstances, there is an obligation on the clinician either to clarify the diagnosis with the pathologist, or to ensure that an equivocating diagnosis will not adversely affect the patient. In some circumstances, this might require that an ambiguous lesion is completely excised, to ensure that it is extirpated. Where the pathological diagnosis is discordant with the clinical diagnosis, the clinician may wish to reconcile the diagnoses by asking the pathologist to review the slides, to examine additional tissue or to seek a further opinion. In Australia, pathology laboratories are obliged to retain pathology slides, tissue and reports for a minimum of seven years, and review of archival material is useful in select cases. This lesion was diagnosed as dysplastic naevus by four pathologists and melanoma by three pathologists. Benign and malignant melanocytic lesions may have features which overlap.

Conclusion

In summary, the diagnosis of naevi and melanomas presents considerable difficulties for the pathologist. In the majority of cases, the diagnosis is straightforward, but in a significant minority of cases, pathological diagnosis is unreliable. Part of the unreliability is an inevitable consequence of the subjective nature of histopathological diagnosis, where different morphological features are given different weights by different observers. However, at least in some circumstances, and using current dermatopathological techniques, morphology is not a perfect predictor of biology. Consequently, the clinician must assess every pathology report in concert with the other clinical information about the patient and about the lesion.

General Practice Pathology is a new fortnightly 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 Dr Simon Clark

Obstetrics and gynaecology

Clinical Articles

Do Not Order These Tests On Pregnant Women

Hot on the heels of the Choosing Wisely campaign of “do nots” for GPs, the Royal Australasian College of Physicians has released a new list of tests doctors should avoid ordering on pregnant women. The recommendations come from the Society of Obstetric Medicine in Australia and New Zealand (SOMANZ), and include the advice that the D-dimer test should not be used to diagnose venous thromboembolism in pregnant women as it is unreliable. Even though women are five times more likely to develop venous thromboembolism in pregnancy, other investigative tests should be used if a clot is suspected as D-dimer concentrations normally rise in pregnancy regardless of whether thrombosis has occurred, making abnormal results ‘incredibly unreliable’. Another recommendation included in the RACP’s top five low value practices and interventions is to not test for inherited thrombophilia in women who have a history of placenta-mediated complications of pregnancy such as stillbirth, recurrent miscarriages or placental abruption. The rationale behind the recommendation is that while some older, retrospective studies had suggested there might be an association with an inherited clotting disorder and these complications, more recent and more robust evidence has shown there is no link and what’s more, taking low molecular weight heparin is not useful as a preventive measure. The experts also advise not to do repeat tests for proteinuria in women with established pre-eclampsia. Even though proteinuria is an important diagnostic marker for pre-eclampsia it is has no prognostic value. The level of the proteinuria does not correlate with the severity of the maternal complications, so repeated testing does not help management. MTHFR testing has become popular in certain, mainly allied health circles and is controversial. SOMANZ has made a strong recommendation to not undertake MTHFR polymorphism tests as part of a routine evaluation for thrombophilia in pregnancy. “Patients with the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) polymorphism are at higher risk of hyperhomocysteinaemia which has been associated with venous thrombosis. However, these associations appear to hold only in countries lacking grain products nutritionally fortified as a public health measure.” They also say testing may lead to many anxiety-provoking false positives, as up to 15% of the population have homozygous variants, which in most instances appear to have no deleterious effects. The final test on the list is the erythrocyte sedimentation rate. The experts advise do not measure ESR in pregnancy as the levels can vary widely depending on factors such as gestational age and haemoglobin concentrations and therefore the test cannot reliably distinguish between healthy and unhealthy women in pregnancy. The list is the latest publication put out as part of the physician-led Evolve initiative run by the RACP. The aim of the initiative is to help ensure high quality patient care by identifying those practices and interventions that represent poor value to patients in terms of improving their clinical outcome and may even cause harm. According to the media release there are now 17 Evolve lists that have been published across a range of medical specialties, and there are another 15 in development. Ref: https://evolve.edu.au/published-lists/society-of-obstetric-medicine-of-australia-and-new-zealand

By Dr Linda Calabresi

Surgery

Clinical Articles

Obesity Surgery – Worth The Money

For most patients in Australia, obesity surgery is an expensive exercise. The surgery alone is likely to see you out of pocket to the tune of several thousand at least. And then there’s the time off work, specialist appointments, follow-up etc etc. So you can understand patients being hesitant about the prospect. And then there’s the worry about effectiveness. Will it work? And if so for how long? Well, new research, published in The New England Journal of Medicine goes a long way to alleviating those fears. The prospective US study, showed that not only did more than 400 severely obese patients who underwent gastric bypass surgery lose a significant amount of weight but that weight loss and the health benefits obtained because of it, were sustained 12 years later. Two years after undergoing the Roux-en-Y surgery, these patients had lost an average of 45kg. Over the following decade there was some weight gain, but at the end of the 12 years the average weight loss from baseline was still a massive 35kg. The impressiveness of this statistic is put into perspective by researchers who compared this cohort with a similar number of severely obese people who had sought but did not undergo gastric bypass. Over the duration of the study this group lost an average of only 2.9kg. And another group, also obese patients who had not sought surgery lost no weight at all on average over this time period. What is even more significant is the difference in morbidity associated with the surgery. The researchers found that of the patients who had type 2 diabetes at baseline, 75% no longer had the disease at two years. And despite the progressive nature of type 2 diabetes, 51% were still diabetes-free at 12 years. In addition, the surgery group had higher remission rates and lower incidence rates of hypertension and lipid disorders. “This study showed long-term durability of weight loss and effective remission and prevention of type 2 diabetes, hypertension and dyslipidaemia after Roux-en-Y gastric bypass,” the study authors concluded. Even though this surgery is done less commonly in Australia than laparoscopic procedures, the reality is that bariatric surgery, for the most part represents enormous value for severely obese patients. The dramatic results and the significant health benefits will no doubt increase pressure on the government and private health insurers to improve access to what could well be described as life-changing surgery. Ref: NEJM 2017; 377: 1143-1155. DOI: 10.1056/NEJMoa1700459

By Dr Linda Calabresi

Diagnostics

Clinical Articles

Testing For Iron

Blood tests for iron status are among the most common requested in clinical medicine. This may be largely justified because of the prevalence of iron deficiency combined with a relatively common genetic condition of haemochromatosis. In Australia, iron deficiency, defined by the Royal College of Pathologists of Australasia (RCPA) as a ferritin level below 30 ug/L, affects only 3.4% of men but 22.3% of women according to the Australian Bureau of Statistics survey in 2011-2012. The issue in women is particularly related to premenopausal women (16-44 years) where 34.1% are iron deficient. This is not surprising when nutrition surveys show that 40% of premenopausal women have inadequate dietary iron intake. Despite this high prevalence, screening with iron studies is not currently recommended in any demographic. While many hospitals include a ferritin in the shared care antenatal panel, most antenatal guidelines assume that an FBE will detect iron deficiency (which is probably wrong). Anaemia is a late stage of iron deficiency and ideally not a stage we should be waiting for. While it is true that microcytosis of red cells is often found in iron deficiency this is unreliable as

thalassaemia also causes microcytosis and

vegetarians usually also have B12 deficiency which causes macrocytosis that ‘cancels out’ the low mean cell volume.

The unevenness (or high red cell distribution width / RDW) is a more sensitive test of early iron deficiency. The association of B12 deficiency and iron deficiency, especially in vegetarians, is so important that clinicians should always think of the other when the other is detected. It is estimated that one in eight Australians carry the predisposition to haemochromatosis. It is most common in British / Celtic peoples (C282Y or H63D are the common HFE gene mutations). When two HFE heterozygotes have children, one in four of the offspring will be homozygote therefore roughly (1/8 * 1/8 * 1/4 =) 1/256 Australian are homozygote - but only half develop disease. This may be because many have been protected from iron overload through diet or blood loss, such as blood donation. Even at a ‘disease’ prevalence of 1:400 to 1:500, haemochromatosis is a relatively common condition with significant potential morbidity that must be considered, especially in all relatives (first degree relatives can be gene tested without iron studies). ‘Iron overload’ is a little more awkward to define than iron deficiency. Serum ferritin levels above the population norms are not necessarily harmful, but if we waited for serum ferritin levels to reach dangerous levels (eg >1000 ug/L), we would not be preventing the sequelae of iron overload such as liver disease, but also a higher risk of cardiovascular disease and premature arthropathy. Most labs have upper clinical decision limits for ferritin of between 200 and 500 ug/L as a sensitive early warning for the possibility of haemochromatosis. Should a high ferritin level be confirmed, gene testing can be rebated according to Medicare Benefit Schedule (MBS) requirements. The pathology tests I have been discussing serum ferritin as the marker of iron stores however clinicians in Australia commonly request ‘iron studies’. Indeed, ferritin is the storage protein for iron that ‘leaks’ out of cells and most accurately reflects cellular iron stores. What is the value of the other two measurements? One of the other measurements is serum iron and it is a bad measure of iron status (we probably shouldn’t report it at all). The serum iron level depends on meals, depends on the time of day (lower in the afternoon) and most importantly, depends on the concentration of the protein that chaperones iron in the circulation: serum transferrin. Patients with higher transferrin levels will generally have higher serum iron levels. What is important is how iron is the transferrin carrying and this is calculated as the ‘transferrin saturation’ (a ratio of serum iron to transferrin). Typically transferrin saturation is at least 10% full, and uncommonly more than 45% full and levels outside this are supportive of iron deficiency and iron overload respectively. While the transferrin saturation calculation corrects some of the unreliability of serum iron, saturation is still subject to diet and supplements and diurnal variation. Clinicians in Australia are used to requesting the full iron study panel of tests. This is useful in iron overload because in haemochromatosis, the earliest change is a high transferrin saturation which may be found years before the ferritin rises above the upper decision limit. A confirmed elevation of transferrin saturation is also allows haemochromatosis gene testing to be MBS rebated. Iron deficiency can be identified by a low serum ferritin (less than 30 ug/L) and the rest of the iron studies may also be altered with low serum iron saturation and higher levels of transferrin. Low serum iron saturation is non-specific (eg diet and afternoon samples) and high transferrin is also non-specific (eg OCP and pregnancy). Unfortunately there are some patients that are misidentified with iron deficiency because of these non-specific tests even when ferritin was clearly normal and there is discussion of banning the ability to request serum iron and transferrin when looking for iron deficiency because of the potential harms in misinterpretation. For clinicians there are even more important confounders than the physiological effects on serum iron and transferrin saturation because when inflammation (the ‘acute phase reaction’) is present the body actually hides away its iron stores by decreasing iron release (low serum iron), decreasing transferrin production (ie negative acute phase reactant), and because iron is no longer being mobilised, it starts accumulating in cells (ferritin rise as if it were an acute phase protein). Unfortunately all the iron studies are therefore unreliable in the presence of inflammation and if there is some suspicion a serum CRP is the most sensitive and specific test to detect inflammation. All we can say otherwise is

that if the ferritin is below 30 ug/L in the presence of inflammation there must be iron deficiency and

(ii) if the ferritin rises above 100 ug/L in the presence of inflammation then there was probably enough iron around anyway.

There is a test that helps separate true iron deficiency in anaemic patients with inflammatory disorders called ‘soluble serum transferrin receptors’ but it is not covered in the Medicare Benefits Schedule although the RCPA have made a submission to government.
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 A/Prof Ken Sikaris

Immunology and allergy

Clinical Articles

New hope for kids with severe food allergies

One of the new class of biologics may have a pivotal role in desensitising children with severe food allergies, US researchers say. That was the conclusion after their placebo-controlled study showed that a preliminary short course of the monoclonal antibody, omalizumab (Xolair) improved the safety and efficacy of oral immunotherapy in children with multiple severe Ig-E mediated food allergies. Admittedly the study was small, involving only 48 children aged 4-15 years, and only looked at children with Ig-E mediated allergies to multiple foods but the implications, the study authors say are important. These patients are a highly atopic population who are at risk of near-fatal or fatal food allergic reactions to multiple foods. There is plenty of evidence that oral immunotherapy is effective for single food desensitisation. However there has been little proof that immunotherapy works in children with allergies to multiple foods, and these are the ones more likely to accidentally ingest a food that may trigger anaphylaxis. Children with multiple food allergies are also far more likely to be unable to tolerate the oral immunotherapy. So in this phase 2 trial, those children in the treatment group were given omalizumab for eight weeks before commencing oral immunotherapy against a range of allergens including peanuts, cows milk and several different tree nuts. Outcomes were assessed by a food challenge at week 36 that looked at the ability to tolerate 2g of the trigger food. At the 36 week mark, 83% of children could now tolerate the allergenic food in the omalizumab-primed group compared with only 33% in the placebo group. It also appeared that omalizumab was well-tolerated with no serious or severe adverse events occurring in those who received it. The impact of these findings on the lives of affected children should not be underestimated, the researchers suggest in The Lancet Gastroenterology and Hepatology. “[The] ability to increase an individual’s threshold of food ingestion to a serving of protein [for example] is important for their nutrition and overall quality of life,” they wrote. The study had its limitations, namely it remains unknown if the desensitisation was sustained but the finding that the anti-IgE cover made the oral immunotherapy more tolerable and therefore more effective is a major though incremental advance in the management of this increasingly prevalent condition. Ref: Lancet Gastroenterology and Hepatology. Published Online Dec 11, 2017 http://dx.doi.org/10.1016/52468-1253(17)30392-8

By Dr Linda Calabresi

Gastroenterology

Clinical Articles

Coeliac disease testing

Coeliac disease is a common disorder affecting the gastrointestinal tract, secondary to an immunologic reaction to gluten. At present it can only be managed by lifelong avoidance of gluten, and thus presents a challenge for patients and their health care professionals.

Epidemiology

Coeliac disease was first characterised in the late 1940s with diarrhoea and failure to thrive in young children. The wartime shortage of wheat, and adoption of a gluten-free surrogate diet, allowed their symptoms to improve. When wheat was re-introduced into their diets their condition worsened again. Initially thought to be a rare disease of children, we now recognise coeliac disease to be prevalent in adults, including the elderly. Data from the UK reveal that the most common age group diagnosed is between 30 and 45, with more people over 60 than those under 16 years (Coeliac UK: www.coeliac.co.uk). The illness occurs in people of European, Turkish, Middle Eastern, Egyptian and Indian backgrounds. It appears to be rare in sub-Saharan Africa and South-East Asia. There is debate over mass screening in populations such as in the UK and Scandinavia, where the disease incidence approaches 1%. The Gastroenterological Society of Australia (GESA) recommends screening in persons with Type 1 diabetes mellitus, Down syndrome, Turner syndrome, immunoglobulin A (IgA) deficiency, or a family history of coeliac disease, where the condition may be as common as 1 in 10.

Immunopathology

The pathologic understanding of coeliac disease has advanced considerably over the past 10 years, although our understanding is still incomplete. In some individuals, when gluten is digested the peptides cross the intestinal mucosa where they are recognised by the mucosa-associated lymphoid tissue. Those individuals with HLA-DQ2 or -DQ8 are able to process the gluten peptides, resulting in presentation of gliadin/gluten peptides on the surface of antigen-presenting cells. Over 99% of coeliac patients have HLA-DQ2 or -DQ8, and homozygotes for DQ2/8 are more likely than heterozygotes to develop the disease, and more severely. For the peptides to be presented to T cells, they must first be deamidated by a ubiquitous enzyme, tissue transglutaminase (tTG). Tissue transglutaminase alters the gluten-derived peptide so that it remains in the binding site of the HLA molecule, and allows an immune response to occur against the enterocytes that carry the HLADQ2/8-gluten peptide complex. Tissue transglutaminase is present in an active form outside cells; its usual role is to help maintain the extra-cellular matrix. Several isoenzymes of tTG exist throughout the body, tTG2 being present in the GI tract. It is the presence of IgA antibodies to this enzyme— anti-tTG2 antibodies (hereafter ‘tTG antibodies’)—that have become the gold standard serologic marker for coeliac disease. It remains uncertain why antibodies to tTG develop in coeliac patients, although research suggests that tTG can become cross-linked to the gluten peptide and cause specific tTG antibodies to develop, through a process termed ‘epitope spreading’. Tissue transglutaminase antibodies have been shown to pre-date the development of the histologic changes of coeliac disease. It is clear that antibodies to tTG are not pathogenic in most patients, as many cells in the body contain similar tTG. However, in dermatitis herpetiformis, a disease long associated with coeliac disease, these antibodies develop against tTG3 (whereas in coeliac disease they are directed against tTG2). In dermatitis herpetiformis, these tTG3 antibodies may well be pathogenic, leading to classic cutaneous lesions.

Serologic testing

IgA tTG antibodies are now considered the gold standard in the detection of coeliac disease, giving a sensitivity of around 95%, and a specificity of around 90%. IgA tTG antibodies become negative 9–12 months after the introduction of a gluten-free diet. In children less than 2 years of age, IgA production is not mature and may result in false negative IgA tTG. This is especially true for those less than one year of age. At present, all serologic diagnoses should be confirmed by histologic diagnosis, as false positives can occur. Although several studies in children have indicated that very high IgA anti-tTG results may not need to be confirmed by biopsy, Australian guidelines indicate the need for histologic confirmation. IgG tTG antibodies may also be detected in coeliac patients, though they have similar problems to IgG anti-gliadin antibodies (AGA, discussed below), with a poor sensitivity and specificity, despite initial enthusiasm for their utility. Older serologic tests for coeliac disease were based on antibodies directed against gliadin—anti-gliadin antibodies (IgA AGA and IgG AGA). Like all food antibodies, they have relatively poor sensitivity (false negatives) and particularly poor specificity (false positives), especially given that they are a group of antibodies (polyclonal), rather than being directed against a single epitope. The indication for IgA AGA is very limited and should largely be consigned to history. However, these antibodies can be used to monitor early adherence to a gluten-free diet as they become negative 6–9 months after the diet is introduced. IgG AGA, however, remains of use in IgA-deficient patients in whom IgA tTG and IgA AGA are not produced. IgG against deamidated gliadin is of use in IgA-deficient patients in whom IgA tTG and IgA AGA are not produced. This is a modified test, using a gliadin peptide (small piece of protein) that had been altered to more closely resemble the natural peptide found in wheat. IgA deficiency is defined as ‘undetectable or barely detectable’ serum IgA. IgG AGA are also of use in children less than two years of age (and especially children under one), in whom the ability to produce IgA antibodies has not fully developed. All patients with IgA deficiency in whom coeliac disease is suspected should undergo a small bowel biopsy, regardless of the IgG AGA and other testing conducted. It is suggested they be referred to a gastroenterologist, as other diseases such as chronic giardia and autoimmune enteritis may occur. One theory to explain why IgA deficiency is associated with the development of coeliac disease is that IgA is involved in the neutralisation of foreign antigens at mucosal surfaces, and these deficient individuals have greater transmucosal passage of gliadin fragments. Another type of antibody, IgA endomysial antibodies, has also been used to test for the disease in the past. These antibodies were first detected in monkey oesophagus; it is now recognised that the antigen being detected by this method was tTG. These antibodies are highly specific (~ 100%) but have a slightly lower sensitivity (~ 90%) than IgA tTG. Endomysial antibodies are sometimes used in children under two years of age.

Tissue typing

In selected cases, HLA-DQ typing may be of benefit. In patients who are predisposed to the development of coeliac disease, a negative test would essentially rule out the diagnosis. A positive result, on the other hand, would not significantly alter the chance of the person having coeliac disease. In Down syndrome and Turner syndrome patients, this would alleviate the need for life-long screening. Tissue typing may be of value in infants (less than two years), to exclude disease, as serologic markers are less reliable. HLA-DQ typing in relatives of coeliac patients may also be of use, although they are highly likely to have DQ2/8 present, whether or not they also have the disease. As DQ2 is independently associated with IgA deficiency and Type 1 diabetes, tissue typing would be less beneficial in such cases.

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 Dr Daman Langguth

Psychiatry

Clinical Articles

Long-term dangers of postnatal depression

There is no debate – postpartum depression can be a devastating disease for a new mother. However, what is probably less well-recognised is the long-term consequences of that illness on the child. The latest findings from an ongoing longitudinal UK study of parents and infants shows that children whose mother was assessed as having moderate to severe depression at both two and eight months after delivery had a substantially increased risk of adverse outcomes across a number of child measures from behaviour and learning to mental health up to 18 years later. The observational study known as the British Avon Longitudinal Study of Parents and Children(ALSPAC) has followed over 9800 women who were pregnant in the early 1990s. In the latest findings, published in JAMA psychiatry, the researchers noted that women who still had moderate to severe depression at eight months postpartum, were likely to still have depression 11 years later. And the children of these women had a four- fold increased risk of behaviour problems as a pre-schooler, twice the risk of being poor at maths in high school and a seven fold increased risk of depression as an adult. Conversely, if the postpartum depression was not persistent at either the moderate or severe level there appeared to be no increased risk of behaviour and learning problems or depression in the offspring, which is reassuring. The study findings published in JAMA psychiatry raise a number of interesting questions. “Having established a highly vulnerable group of mothers still does not answer the question of what to do about interventions, or who, when, or how to treat,” the author of an accompanying editorial says. The design of the study meant the researchers were unable to determine the effects of maternal treatment on reducing postpartum depression and improving child outcomes. As the editorial author also points out, there is also considerable debate whether treatment should focus mainly on the mother and her illness or be directed at the mother-infant relationship. Nonetheless, it is clear that, as a first step at least, these mothers with persistent severe depression need to be identified. Screening for depression which now focuses on pregnancy and the immediate postpartum period needs to be extended to a year after delivery. “Screening both early and late in the first postpartum year will enable the identification of women with persistent [postnatal depression] and thus the offer of appropriate treatment,” the study authors concluded. Ref: JAMA Psychiatry doi:10.1001/jamapsychiatry.2017.4363 doi:10.1001/jamapsychiatry.2017.4265

By Dr Linda Calabresi

Infectious diseases

Clinical Articles

Here’s what you need to know about the new flu vaccines for over-65s

In an attempt to avoid a repeat of last year’s horror flu season, Health Minister Greg Hunt yesterday announced the government would fund two new flu vaccines in 2018 to try to better protect the elderly. While influenza affects people of all ages, infections among the elderly are more likely to require hospitalisation or cause serious complications such as pneumonia and heart attacks. Of the 1,100 Australians who died last year from flu-related causes, 90% were aged 65 and over. The two free vaccines for over-65s work in different ways: FluZone High Dose is a high-dose version; Fluad adds an additional ingredient to boost its effectiveness. Both are recommended for use only in people aged 65 and over. But neither is perfect. And it’s important to remember flu vaccines are, at best, only partially protective.

Why do we need new vaccines for flu?

Australia’s National Immunisation Program provides free influenza vaccine for the elderly, as well as other high-risk groups including pregnant women, those with chronic diseases and Indigenous Australians.

Read more: Flu vaccine won't definitely stop you from getting the flu, but it's more important than you think

Older people’s immune systems don’t respond to flu vaccines as well as younger people’s. Recent studies have also shown that flu vaccines don’t appear to be as effective in the elderly at protecting against flu and its complications. Compounding this problem is that the flu subtype that tends to affect older people (A/H3N2) is different to that which affects younger people (A/H1N1). Although the seasonal flu vaccine now contains four strains to cover all the relevant subtypes present, the protection against H3N2 infection appears to be poorer than against other strains. Two strategies are attempting to improve the effectiveness of flu vaccines. One is to increase the dose of the flu strains in the vaccine. This is the basis for Sanofi’s High Dose FluZone vaccine, which contains four times the amount of flu antigen than the standard dose. Another way is to add a substance that improves the immune response, known as an adjuvant, in combination with the flu strains. This is the basis for Seqirus’ (CSL) Fluad vaccine, which contains the adjuvant MF59. This vaccine has been used overseas for many years, but has only been become available in Australia this year.

How much better are these vaccines than the current vaccine?

Compared to the standard flu vaccine, the high-dose version has been shown to better stimulate the immune system of older users to make protective antibodies. It has been shown to better reduce rates of flu infection in over-65s than the standard vaccine. And, interestingly, it also seems to protect against pneumonia. One common criticism of clinical trials is that they don’t include the types of people who are found in the “real world”. But population based observational studies suggest that the high-dose vaccine is more protective than the standard-dose vaccine where H3N2 is the predominant circulating strain – as it was last year.

Read more: Here's why the 2017 flu season was so bad

What about the Fluad (adjuvanated) vaccine? Compared to the standard vaccine, adjuvanted flu vaccine has been shown to better stimulate the immune system of older users to make protective antibodies. Unlike the high-dose vaccine, there have not been clinical trials that show a difference in infection rates compared with the standard vaccine. But observational data suggests the adjuvanted vaccine is more protective against hospitalisation with influenza or pneumonia – to a similar degree as the high-dose vaccine. One problem with both these vaccines is that they only contain three strains, rather than the four strains in the current vaccine. The strain missing from the new vaccines is an influenza B type. But the benefits of better protection against the most common three strains in the new vaccine appear to outweigh the potential loss of protection against the missing B strain.

Are the new vaccines safe?

Both vaccines are safe, but commonly cause mild side effects, and very rarely can cause serious side effects. However, these risks from the vaccine are less than from getting influenza infection. The main side effect of vaccines relates to their effect in stimulating the immune system. In many people they cause a sore arm and, less commonly, a fever. The side effects of these new flu vaccines are slightly more common than with standard vaccines. Generally, these side effects are mild and don’t last long. None of the flu vaccines used in Australia contains live virus and therefore can’t cause flu infection. However, the vaccination season (April to June) usually occurs around the same time as when another respiratory virus (RSV) circulates, so this respiratory infection is commonly misattributed to vaccination.

Read more: Health Check: when is 'the flu' really a cold?

Rare but serious side effects, such as Guillain Barre Syndrome (where the immune system attacks nerves), have been described after flu vaccination. Studies suggest that the risk of these side effects are less common after the flu vaccine than after flu infection. People with allergies should discuss flu vaccines with their doctor. In the past, there has been concern that the flu vaccines, which are manufactured in eggs, may elicit allergic reactions in people with egg allergy. However, it is now thought that people with egg allergies can receive flu vaccines safely under appropriate supervision. In 2009, an adjuvanted vaccine (Pandemrix) was thought to be implicated in cases of narcolepsy (a disease associated with excessive sleepiness) in Europe. However, this primarily occurred in children (rather than the elderly), and with a different adjuvant (ASO3) than is being used in Fluad (MF59)

Which vaccine should I get?

The two vaccines have not been compared head to head, so it isn’t known which one is better. The available data suggest they are similar to each other. In practice, what vaccine you’ll receive will depend on what’s available at your GP or pharmacy. It is important to note that these vaccines are only recommended for use in people 65 years of age or older, and are not recommended for use in people under this age. The standard vaccine will still be available for younger people. There are no data to support the use of multiple doses of vaccines of the same or different types.

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Neither of the new vaccines is perfect – they simply reduce your risk of getting flu to a slightly greater effect than the standard vaccine. Like other flu vaccines, there is still the chance that the vaccine strains don’t match what’s circulating. Despite the common perception that the flu is mild illness, it causes a significant number of deaths worldwide. To make an impact on this, we need better vaccines, better access to vaccines worldwide and new strategies, such as increasing the rate of vaccination in childhood. Allen Cheng, Professor in Infectious Diseases Epidemiology, Monash University This article was originally published on The Conversation. Read the original article.

By Prof Allen Cheng