Immune system diseases

Elevated serum angiotensin‐converting enzyme (ACE) activity, a biomarker for epithelioid granuloma, has a supportive role in the diagnosis and management of sarcoidosis,1 although in population‐based studies its diagnostic usefulness is modest, with positive and negative predictive values of 25.4% and 89.9% respectively.2 Further, elevated ACE activity is non‐specific; it is also found in people with tuberculous and other infectious granulomata, liver disease, lymphoma, diabetes, or hyperthyroidism, and also as a benign familial condition. However, elevated ACE activity can facilitate some clinical decisions, including the diagnosis of Löfgren syndrome or adults with uveitis.1,3 Serum ACE can be assessed by measuring its enzymatic activity or its protein concentration. Most Australian pathology laboratories measure ACE activity, which is predictably inhibited by ACE inhibitor (ACEI) drugs commonly prescribed for people with high blood pressure,4,5 whereas ACE protein level is not affected by these agents. In this study, we investigated the prevalence of ACEI influencing ACE activity results; for cases of markedly elevated ACE, we also evaluated the clinical performance of the two ACE measures with respect to sarcoidosis. In a preliminary evaluation, all discrepant paired results (high mass with low activity) were for patients using ACEIs at the time of sample collection. Between January 2017 and February 2019, we measured ACE activity and protein concentration in parallel; all test requests were initiated by clinicians as part of routine clinical care. Formal ethics approval was not required for collecting and analysing data to assess the quality of routine care. Further details of the study design and laboratory methods are included in the online Supporting Information. A total of 8882 paired test results were retrieved from the Pathology Queensland database for 4206 women (median age, 53.3 years; interquartile range [IQR], 36.0–65.6 years) and 4014 men (median age, 55.2 years; IQR, 42.2–67.3 years). Two discrete populations were evident in the scatterplot of paired results; for 1346 pairs (15.2%; 95% CI, 14.4–15.9%; green in Box 1), ACE activity was low relative to ACE protein, pathognomonic of ACEI interference. The upper reference limits for the two tests and the regression line for samples not affected by ACEIs nearly intersected, suggesting the general biologic equivalence of the two analytic methods and that the discordant results were not attributable to mismatched reference limits (Box 1). The correlation of values for the unaffected samples was moderate (R2 = 0.71) and the differences between the methods greater than predicted by their variances (Supporting Information, figure), indicating that the assays were not interchangeable. The monthly rate of ACEI interference was fairly consistent throughout the study period, despite comments to requesting physicians about the discrepancy between activity and protein levels included in pathology laboratory reports (Box 2). Of the 50 patients with high ACE protein levels (more than 300 μg/L) and ACE activity below the upper reference limit (70 IU/L), 27 (54%; 95% CI, 40–67%) had sarcoidosis (including 16 with ACE activity below the lower reference limit of 20 IU/L). In contrast, four of 16 people (25%; 95% CI, 10–50%) with high ACE activity (greater than 100 IU/L) and ACE protein within the reference interval had sarcoidosis. From a diagnostic perspective, ACEIs erode the negative predictive value of ACE activity, the most useful characteristic of this biomarker (Box 1; Supporting Information, table). Given that ACEI therapy interferes with ACE activity assessment, we recommend measuring ACE protein in routine practice, with the added benefit of convenience and safety of uninterrupted therapy for people taking ACEIs. The lack of influence of laboratory comments on testing behaviour is disappointing, but perhaps unsurprising given the information overload typical of modern medicine.6 Box 1 – Effect of angiotensin‐converting enzyme inhibitor (ACEI) therapy on serum ACE activity: scatterplot of paired ACE activity and protein assay results Pathology test reference intervals are indicated by the dotted lines. The shaded areas indicate result pairs included in the clinical audit (numbers of patients with sarcoidosis/total number audited). Blue: ACE activity not affected by ACEI therapy; 7536 samples, R2 = 0.71. Green: ACE activity affected by ACEI therapy; 1346 samples, R2 = 0.21. Box 2 – Influence of angiotensin‐converting enzyme (ACE) inhibitor (ACEI) therapy on serum ACE activity, by month

Carel J Pretorius · Jacobus PJ Ungerer

Advice for clinicians managing patients with cancer during the pandemic

Robert Weinkove · Zoe K McQuilten · Jonathan Adler · Meera R Agar · Emily Blyth · Allen C Cheng · Rachel Conyers · Gabrielle M Haeusler · Claire Hardie · Christopher Jackson · Steven W Lane · Tom Middlemiss · Peter Mollee · Stephen P Mulligan · David Ritchie · Myra Ruka · Benjamin Solomon · Jeffrey Szer · Karin A Thursky · Erica M Wood · Leon J Worth · Michelle K Yong · Monica A Slavin · Benjamin W Teh

The prevalence of food allergy among Victorian children is rising.1 In Victoria, children with suspected food allergies can be on hospital outpatient clinic waiting lists for months before being assessed.2 This may lead families to consider alternative avenues, which can lead to poor allergy management and the need for emergency care. Increasing numbers of Victorian children are presenting to emergency departments,3 but we do not know whether the number visiting with food allergy is also rising. We analysed Victorian Emergency Minimum Dataset (VEMD) data for the period 2005–06 to 2014–15. The VEMD is a statewide administrative dataset that includes non‐identifiable patient‐level data for all Victorian public emergency department encounters. We included all food allergy‐related presentations by children and young people aged 0–19 years, selected according to International Classification of Diseases, tenth revision, Australian modification (ICD‐10‐AM) codes: T78.0 (anaphylactic shock due to a food reaction), T78.1 (other adverse food reactions, not elsewhere classified), T78.4 (allergy, unspecified: includes non‐food‐related allergies), and L27.2 (dermatitis due to ingested food). Presentation rates by age group were calculated using Australian Bureau of Statistics (ABS) age‐stratified population data for Victorians aged 0–19 years;4 rates for regions were calculated using ABS population data for Statistical Areas 2 (SA2).5 The study was deemed exempt from the need for formal ethics approval by the Royal Children's Hospital Human Research Ethics Committee. The number of children presenting to emergency departments with food allergy‐related problems increased from 2368 in 2005–06 to 4263 in 2014–15; the presentation rate increased from 18 to 29 per 10 000 population (Box 1). About half the children who presented with food allergy‐related problems were aged 0–4 years, the rate for this age group increasing from 38 to 55 per 10 000 population (Box 2). The proportion of presentations triaged as being more urgent (triage categories 1–3) also increased, from 51% to 63% (Box 1). The rate of presentations to metropolitan hospitals increased more (from 18 per 10 000 in 2005–06 to 32 per 10 000 in 2014–15; 78% increase) than did the rate for rural hospitals (26 per 10 000 in 2005–06 to 36 per 10 000 in 2014–15; 38% increase) (Box 1). Hospitals in the North‐West Melbourne region received about one‐third of all allergy‐related emergency department visits, and the number in this region doubled over the study period (706 in 2005–06; 1536 in 2014–15) (Box 3). These data indicate that the demand for emergency services associated with food allergy‐related problems in children increased during 2005–15. The increase was particularly marked for children aged 0–4 years and for children and young people in the North‐West Melbourne and Southern Melbourne regions. While the reason for the increased burden is not clear — that is, whether the prevalence of allergy had increased (including because of a change in population composition), management plans had changed, or access to community services was reduced — the consequence is greater demand on emergency services across Melbourne. Box 1 – Presentations to Victorian public emergency departments by childen and young people (0–19 years) with food allergy‐related problems 2005–06 2006–07 2007–08 2008–09 2009–10 2010–11 2011–12 2012–13 2013–14 2014–15 All food allergy presentations Number 2368 2680 2754 2991 3082 3159 3185 3422 3881 4263 Rate (per 10 000 population)* 18 20 21 22 23 23 23 24 27 29 ICD‐10‐AM diagnostic codes T78.0 141 (6.0%) 152 (5.7%) 154 (5.6%) 168 (5.6%) 233 (7.6%) 283 (9.0%) 289 (9.1%) 339 (9.9%) 437 (11.3%) 501 (11.8%) T78.1 800 (33.8%) 948 (35.4%) 962 (34.9%) 1127 (37.7%) 1167 (37.9%) 1152 (36.5%) 1117 (35.1%) 1288 (37.6%) 1464 (37.7%) 1624 (38.1%) T78.4 1234 (52.1%) 1351 (50.4%) 1441 (52.3%) 1488 (49.8%) 1552 (50.4%) 1597 (50.6%) 1633 (51.3%) 1702 (49.7%) 1881 (48.5%) 2031 (47.6%) L27.2 193 (8.2%) 229 (8.5%) 197 (7.2%) 208 (7.0%) 130 (4.2%) 127 (4.0%) 146 (4.6%) 93 (2.7%) 99 (2.6%) 107 (2.5%) Age Number 0–4 years 1202 (50.8%) 1364 (50.9%) 1424 (51.7%) 1537 (51.4%) 1520 (49.3%) 1595 (50.5%) 1593 (50.0%) 1759 (51.4%) 2015 (51.9%) 2152 (50.5%) 5–9 years 466 (19.7%) 515 (19.2%) 521 (18.9%) 573 (19.2%) 673 (21.8%) 608 (19.3%) 660 (20.7%) 702 (20.5%) 813 (21.0%) 967 (22.7%) 10–14 years 305 (12.9%) 335 (12.5%) 355 (12.9%) 405 (13.5%) 403 (13.1%) 426 (13.5%) 383 (12.0%) 433 (12.7%) 515 (13.3%) 561 (13.2%) 15–19 years 395 (16.7%) 466 (17.4%) 454 (16.5%) 476 (15.9%) 486 (15.8%) 530 (16.8%) 549 (17.3%) 528 (15.4%) 538 (13.8%) 583 (13.7%) Rate (per 10 000 population)* 0–4 years 38 42 43 45 43 45 44 47 53 55 5–9 years 15 16 16 18 21 18 19 20 22 26 10–14 years 9 10 11 12 12 13 12 13 15 16 15–19 years 12 13 13 13 14 15 15 15 15 16 Sex Number Boys 1284 (54.2%) 1435 (53.5%) 1476 (53.6%) 1625 (54.3%) 1663 (54.0%) 1723 (54.5%) 1779 (55.9%) 1867 (54.6%) 2158 (55.6%) 2388 (56.0%) Girls 1084 (45.8%) 1245 (46.5%) 1278 (46.4%) 1366 (45.7%) 1419 (46.0%) 1436 (45.5%) 1406 (44.1%) 1555 (45.4%) 1723 (44.4%) 1875 (44.0%) Rate (per 10 000 population)* Boys 19 21 21 23 24 25 25 26 29 32 Girls 17 19 20 21 21 22 21 22 24 26 Hospital region Number Metropolitan† 1560 (65.9%) 1860 (69.4%) 1907 (69.2%) 2008 (67.1%) 2071 (67.2%) 2194 (69.5%) 2186 (68.6%) 2345 (68.5%) 2781 (71.7%) 3149 (73.9%) Rural‡ 808 (34.1%) 820 (30.6%) 847 (30.8%) 983 (32.9%) 1011 (32.8%) 965 (30.5%) 999 (31.4%) 1077 (31.5%) 1100 (28.3%) 1114 (26.1%) Rate (per 10 000 population)* Metropolitan† 18 22 22 23 23 25 24 25 29 32 Rural‡ 26 27 27 32 33 31 32 35 35 36 Triage category Categories 1–3 1198 (50.6%) 1429 (53.3%) 1568 (57.0%) 1707 (57.0%) 1830 (59.3%) 1861 (59.0%) 1807 (56.8%) 2047 (59.8%) 2365 (61.0%) 2694 (63.2%) Categories 4, 5 1170 (49.4%) 1251 (46.7%) 1186 (43.0%) 1284 (43.0%) 1252 (40.7%) 1298 (41.0%) 1378 (43.2%) 1375 (40.2%) 1516 (39.0%) 1569 (36.8%) ICD‐10‐AM = International Classification of Diseases, tenth revision, Australian modification. * All presentation rates are per 10 000 children in Victoria aged 0–19 years in the corresponding category. † Victorian Emergency Minimum Dataset (VEMD) regions: North‐West, Southern, and Eastern Melbourne. ‡ VEMD regions: Loddon Mallee, Gippsland, Barwon South West, Hume, Grampians. Box 2 – Presentations to Victorian public emergency departments by people aged 0–19 years with food allergy‐related problems: rates per 10 000 population, by age group Box 3 – Presentations to Victorian public emergency departments by people aged 0–19 years with food allergy‐related problems, by hospital campus region

Rachel O'Loughlin · Harriet Hiscock

To the Editor: Thiopurines are used in oncology, immunology and inflammatory bowel disease (IBD). In the coronavirus disease 2019 (COVID‐19) pandemic, patients taking thiopurines face uncertainty as to the risk of serious complications or death if infected. Traditionally, thiopurine use has been associated with an increased risk of opportunistic viral infections.1,2,3 A large IBD registry study found that using thiopurines and having active disease were associated with a higher risk of serious viral infection.3 However, all identified causative agents were species of the Herpesviridae genus.1,2,3 The risk associated with thiopurine use can therefore not yet be generalised to other virus genera, and indeed only corticosteroid use is associated with risk of contracting influenza in patients with IBD.4 COVID‐19 is caused by a novel coronavirus — the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) — and there are no available data from previous coronavirus strains such as SARS‐CoV or Middle East respiratory syndrome coronavirus (MERS‐CoV) to allow for estimation of risk in patients taking thiopurines.3,5 Although, intuitively, immunosuppression with thiopurines may increase the risk from COVID‐19, there are in vitro and in silico data to suggest that thiopurines constrain maturation of MERS‐CoV via inhibition of a viral protease.5 Although this study has not been replicated for COVID‐19 or progressed into animal models, it does raise the possibility that thiopurines use may not necessarily increase the risk of contracting COVID‐19. Thiopurine withdrawal is associated with a 12‐month relapse rate of 17–53% in patients with Crohn's disease and 11–77% in patients with ulcerative colitis.6 This is an important consideration in COVID‐19, as disease relapse requiring steroid use has previously been associated with increased risk of viral complications.3,4 The consequences of thiopurine withdrawal due to COVID‐19 are not yet clear and this information is eagerly awaited as many centres collect prospective data. Preliminary data from SECURE‐IBD — a COVID‐19 database for IBD — report 87 COVID‐19 cases to date in patients taking thiopurines, of whom 52 were managed as outpatients and 35 were admitted to hospital, with two reported deaths.7 These evolving data provide cautious support for the relative safety of thiopurines but cannot be interpreted conclusively in the setting of the rapidly evolving situation. Perhaps the best advice we can currently offer patients is that effective control of disease may carry less risk than poorly considered withdrawal of therapy. The Gastroenterological Society of Australia has issued recommendations that the minimum level of immunosuppression should be continued to control disease although a drug holiday may be considered in some patients with long term stable disease.8 This dilemma highlights the importance of online registries to gather vital data as we work together as a profession to provide evidence‐based advice for our patients during this pandemic.

Thomas M Goodsall · Samuel P Costello · Robert V Bryant

Psoriasis is a chronic inflammatory disease that is commonly encountered in primary care and is associated with significant morbidity that extends beyond the skin manifestations. Psoriasis is associated with an elevated risk of psoriatic arthritis, cardiovascular disease, obesity, insulin resistance, mental health disorders, certain types of malignancy, inflammatory bowel disease and other immune‐related disorders, and hepatic and renal disease. Enhanced recognition of these comorbidities may lead to earlier diagnosis and potentially better overall health outcomes. Psoriatic nail involvement, severe skin disease and obesity are associated with a greater risk of psoriatic arthritis. Individuals with psoriasis should be routinely screened for psoriatic arthritis to allow for early intervention to improve long term prognosis. Life expectancy is reduced in people with psoriasis due to a variety of causes, with cardiovascular disease and malignancy being the most common aetiologies. Psoriasis affects several factors that contribute to worsened quality of life and increased risk of depression and anxiety. Effective therapies are now available that have been shown to concurrently improve skin disease, quality of life and psychiatric symptoms. As the concordance between psychosocial impact and objective disease severity does not always correlate, it is essential to tailor management strategies specifically to the needs of each individual. Cigarette smoking and excess alcohol consumption are among the most important modifiable risk factors that increase the likelihood of psoriasis development and severity of skin disease. This provides a compelling rationale for smoking cessation and limiting alcohol intake in people with psoriasis beyond their traditional harmful health consequences.

Tom Kovitwanichkanont · Alvin H Chong · Peter Foley

An 80- year- old man presented with 2 days of fever and a widespread, itchy, nonblanching, erythematous rash involving more than 50% of body

David WJ Griffin · Genevieve E Martin · Catriona McLean · Allen C Cheng · Michelle L Giles

It may soon be possible to reverse the increase in food allergy of the past few decades

Rachel L Peters · Kirsten P Perrett

SmartStartAllergy faccilitates monitoring of infant feeding practices in primary care and parent-reported reactions to food

Michael O'Sullivan · Sandra Vale · Richard KS Loh · Jessica Metcalfe · Karin Orlemann · Sandra Salter · Ian Peters · Alan Leeb

A 76- year- old man from rural Victoria presented with 4 months of difficulty swallowing due to a painful, large, non-healing tongue ulcer

Michael B MacIsaac · Sasha R Fehily · Stephen Muhi · Linda Yang · Penelope A McKelvie · Cameron J Jeremiah · Barbara Demediuk

Excisional biopsy remains the most appropriate diagnostic biopsy technique for invasive melanoma

Sara L de Menezes · John W Kelly · Rory Wolfe · Helen Farrugia · Victoria J Mar

Antithrombotic treatment is gold standard and effective

Veronica Mezhov · Julian D Segan · Huyen Tran · Flavia M Cicuttini

A 26- year- old man presented to the (ED) overnight with severe and disabling abdominal pain

David J Holland · Michael J Holland

A 59- year- old woman with carbimazolerefractory Graves disease presented with fever and extensive necrotising rash 2 weeks after commencing propylthiouracil therapy

Brian Lam · Alexander Yuile · Suran L Fernando

Evidence suggests that appropriate hepatitis B virus (HBV) screening before B cell-depleting therapy is frequently not performed

Sanjivan Mudaliar · Ken Liu · Simone I Strasser

Testing for hepatitis B in all patients with haematological and solid tumour malignancies, and prophylactic treatment in for people with chronic HBV or past exposure to HBV, is recommended to avoid HBV reactivation during cancer therapy

Joseph Doyle · Michelle Raggatt · Monica Slavin · Sue‐Anne McLachlan · Simone I Strasser · Joseph J Sasadeusz · Jessica Howell · Krispin Hajkowicz · Harshal Nandurkar · Anna Johnston · Narin Bak · Alexander J Thompson

Due to the remarkable improvements in the diagnosis and management of myeloma over the past decade, we can look forward to regimens that will allow the eradication of residual disease and result in the cure of myeloma

Douglas E Joshua · Christian Bryant · Caroline Dix · John Gibson · Joy Ho

Despite pregnancy being identified as a time of increased HIV susceptibility, with risks to both the mother and unborn infant of HIV acquisition, there is a paucity of guidelines, eligibility criteria and risk assessment tools pertaining specifically to the usage of PrEP in pregnancy and lactation. Existing local and international guidelines suggest a low threshold for the initiation of PrEP in serodiscordant HIV‐negative women. It is imperative that the needs of such patients be met through the implementation of strategies to enable appropriate and timely prescription of PrEP.Moreover, with the commencement of availability of Pharmaceutical Benefits Scheme‐subsidised PrEP, the financial and practical obstacles to PrEP provision will be reduced and a subsequent increase in patient awareness and acceptance of PrEP is anticipated. However, the logistics and responsibility of providing PrEP and subsequent necessary follow‐up for pregnant and lactating women at risk of HIV infection has not been sufficiently considered or formalised (ie, general practice versus antenatal clinic).We therefore recommend development of multidisciplinary guidelines on the prevention of mother‐to‐child transmission of HIV among Australian pregnant and lactating women. These guidelines should include information about PrEP. Development of the guidelines must also engage with clinicians treating male patients to ensure that uninfected female partners of child‐bearing potential are not forgotten. The guidelines will require multidisciplinary input including expertise in the areas of HIV, obstetrics, midwifery, general practice and paediatrics, and commitment to: outlining the appropriate circumstances for the provision of PrEP during peri‐conception, pregnancy and lactation; creation of behavioural eligibility criteria and risk assessment tools which recognise the risks specific to pregnant and lactating women; outlining the appropriate follow‐up of patients commenced on PrEP during pregnancy and lactation; defining the setting in which PrEP will be prescribed and post‐prescription surveillance will be undertaken for the pregnant and lactating patient cohort; targeted education of health professionals tasked with the provision of PrEP to the pregnant and breastfeeding patient group; and creation of patient information resources to maximise serodiscordant couple awareness of the requirement for pre‐conception counselling and treatment options available. We believe such a framework is vital to guide and empower medical professionals in the appropriate usage of PrEP in this patient cohort and ultimately provide the best patient care.

Lisa Horgan · Christopher C Blyth · Asha C Bowen · David A Nolan · Andrew P McLean‐Tooke

The known Treatment of people infected with human immunodeficiency virus (HIV) soon after diagnosis reduces the risk of transmission and HIV‐related morbidity. The proportion and characteristics of people who receive early treatment are not well described.

Hamish McManus · Denton Callander · Basil Donovan · Darren B Russell · Catherine C O'Connor · Stephen C Davies · David A Lewis · Margaret E Hellard · Marcus Y Chen · Kathy Petoumenos · Rick Varma · Aaron Cogle · Mark Alastair Boyd · Andrew Grulich · James Pollard · Nick Medland · Christopher K Fairley · Rebecca J Guy

ANA by indirect immunofluorescence remains the method of choice for screening patients suspected of having SARDs. A positive ANA test should be followed by further testing for ENA and dsDNA antibody testing for defining the ANA specificities and disease associations. The presence of anti‐DFS70 antibody in absence of ENA and dsDNA antibodies effectively excludes a diagnosis of SARD.

Pravin Hissaria · Andrew Broadfoot · Karl W Baumgart

Recent international consensus guidelines provide a more rigorous approach to diagnosis, introducing a system of major and minor criteria to facilitate early and accurate diagnosis and to guide diagnostic food challenge. They highlight the need for rapid fluid resuscitation in emergency presentations and the increasing evidence for the use of ondansetron in acute management. Diagnostic challenges should be performed in settings with suitable resuscitation facilities. Action plans and dietary information consistent with this guideline are available via ASCIA.10It is likely that improved understanding of the immunological basis of FPIES will, in the future, facilitate the development of a sensitive and specific biomarker. Until that time, use of standardised diagnostic criteria, improved recognition, timely fluid resuscitation, avoidance of trigger foods, and education form current best practice.

Sam Mehr · Dianne E Campbell

Food allergy has been increasing in incidence worldwide, with rates in Australia the highest in the world

Preeti A Joshi · Jill Smith · Sandra Vale · Dianne E Campbell

A 71-year-old man taking immunosuppressive medication for a renal transplant developed four chronic lower leg ulcers over 6 months

Emily R Sideris · Ludi Ge

The emphasis on prompt diagnosis and treatment of irritable bowel disease offers the possibility of altering the natural history of disease and reducing disability

Emily K Wright · Nik S Ding · Ola Niewiadomski

Well designed and accessible electronic health records, national registries of verified drug reactions, and validated medical alerting devices may assist in the effective communication of drug allergy information

Michaela Lucas · Richard KS Loh · William B Smith