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An unexpectedly high prevalence of undiagnosed diabetes in patients awaiting lung transplantation
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ORIGINAL CLINICAL SCIENCE
An unexpectedly high prevalence of undiagnosed diabetes in patients awaiting lung transplantation Kathryn L. Hackman, MBBS, FRACP,a,b Gregory I. Snell, MBBS, PhD, FRACP,b,c and Leon A. Bach, MBBS, PhD, FRACPa,b From the aDepartment of Endocrinology and Diabetes, The Alfred Hospital, Melbourne; bDepartment of Medicine (Alfred), Monash University, Melbourne; and the cLung Transplant Service, The Alfred Hospital, Melbourne, Victoria, Australia.
KEYWORDS: lung transplantation; diabetes mellitus; prevalence; oral glucose tolerance test
BACKGROUND: Diabetes mellitus (DM) is a common complication after lung transplantation but its prevalence prior to transplantation has not been determined. We sought to determine the prevalence of and risk factors for DM in adults awaiting lung transplantation and to determine whether pre-transplant DM could be diagnosed by hemoglobin A1c (HbA1c) alone. METHODS: All patients wait-listed for lung transplantation over a 2-year period had HbA1c measured. Those not known to have DM also underwent an oral glucose tolerance test (OGTT) with insulin levels. RESULTS: Of 190 patients listed for lung transplantation, 30 (16%) had been diagnosed previously with DM. Twelve patients received transplants and 1 came off the waiting list before having an OGTT. The remaining patients underwent OGTT: 14 were newly diagnosed with DM and 29 with pre-diabetes. One patient vomited during the test and was excluded from analyses. Thus, 41% of all screened waiting list patients had DM (known or newly diagnosed) or pre-diabetes. Neither age, BMI, prednisolone dose nor family history correlated with dysglycemia. Patients with newly diagnosed DM and pre-diabetes were more insulin-resistant than those with normoglycemia. HbA1c correlated poorly with OGTT. CONCLUSIONS: Patients awaiting lung transplantation have unexpectedly high rates of DM and prediabetes despite close medical follow-up. Screening for DM with an OGTT will allow early intervention, which may improve outcomes after transplantation. J Heart Lung Transplant 2013;32:86–91 r 2013 International Society for Heart and Lung Transplantation. All rights reserved.
Few studies have prospectively assessed the incidence of diabetes mellitus (DM) prior to transplantation and none have prospectively assessed its incidence in patients awaiting lung transplantation. The high incidence of DM after solid-organ transplantation is generally assumed to be of new onset, occurring as a complication of immunosuppressive agents including glucocorticoids and calcineurin inhibitors.1–5 The annual number of lung transplantation procedures performed in Australia6 and worldwide7 has increased significantly over the past decade. Although life expectancy Reprint requests: Leon A. Bach, MBBS, PhD, FRACP, Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne 3004, Victoria, Australia. Telephone þ61-3-9076-2460. Fax: þ61-3-9076-3782. E-mail address: [email protected]
has improved in recent years, it is still lower than that of other solid-organ transplants. Diabetes is a significant risk factor for mortality at both 1 and 5 years after lung transplantation,7 and lung transplant recipients have a particularly high incidence of post-transplant DM as they require prolonged, high-dose treatment with diabetogenic immunosuppressants. However, these patients may already be at increased risk of DM prior to transplantation. For example, patients awaiting transplantation due to chronic obstructive lung disease (COPD) may already be taking glucocorticoids, whereas patients with cystic fibrosis (CF) may have impaired pancreatic endocrine function. Many units assess patients for diabetes with a fasting or random blood glucose level or hemoglobin A1c (HbA1c)
1053-2498/$ - see front matter r 2013 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2012.10.010
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Undiagnosed Diabetes in Lung Tx
test. These tests are quick and simple. However, the current gold standard for DM diagnosis is the oral glucose tolerance test (OGTT). Not only does it have a higher sensitivity than HbA1c for detecting DM, it is the only way to diagnose impaired glucose tolerance, which is associated with an increased risk of diabetes and cardiovascular disease. The OGTT may be used less frequently as it takes 2 hours and requires several blood samples. In this study we aimed to determine the prevalence of abnormal glycemic control (DM, impaired glucose tolerance or impaired fasting glucose) and the risk factors for dysglycemia in patients awaiting lung transplantation. We also assessed whether the diagnosis of DM could be simplified with the use of a single, non-fasting blood test—the HbA1c—rather than the standard OGTT.
87 although some patients were tested at their local pathology service. Prednisolone dose was recorded at the time of OGTT. Patients were asked about family history of diabetes. The homeostasis model assessments of insulin resistance (HOMA-IR) and beta-cell function (HOMA-B) were calculated from baseline fasting glucose and insulin levels on the OGTT. The simplified HOMA equations10 for insulin resistance and beta-cell function, where FPI is fasting plasma insulin concentration (mU/ liter) and FPG is fasting plasma glucose (mmol/liter), were used: HOMA-IR¼ ðFPI FPGÞ=22:5 HOMA-Bð%Þ ¼ ð20 FPIÞ=ðFPG-3:5Þ Glucose was measured by the hexokinase method and insulin by the chemiluminescent microparticle-enhanced immunoassay (CMIA) on an Abbott Architect ci16 200 (Abbott Diagnostics, Abbott Park, IL). HbA1c was measured by boronate affinity highperformance liquid chromatography (CLC 330; Primus Diagnostics, Kansas City, MO).
Methods Definitions Patients All patients aged 418 years (n ¼ 190), who were on the waiting list for lung transplantation at The Alfred Hospital, Melbourne, from August 1, 2010 to July 31, 2012 and who had not received a prior solid-organ transplant, were evaluated for DM. Patients were placed on the waiting list according to international guidelines for recipient suitability.8 Twelve patients who proceeded to transplantation, 1 who withdrew from the waiting list before OGTT and 1 who vomited during the OGTT were excluded from subsequent analyses (Figure 1). Patient demographics and underlying diagnoses were obtained from medical records. The study was reviewed and approved by the ethics committee of The Alfred Hospital.
Approach to study To determine pre-transplant diabetes status, all patients not known to have DM underwent a standard 2-hour 75-g OGTT after an overnight fast. Insulin levels were measured on each blood sample (0, 1 hour and 2 hours). The HbA1c, standardized to the Diabetes Control and Complications Trial (DCCT) assay,9 was also measured. Most tests were performed at The Alfred Hospital,
The 2006 World Health Organization criteria11 were used to diagnose DM, venous fasting plasma glucose Z7.0 mmol/liter or 2hour glucose Z11.1 mmol/liter; impaired glucose tolerance (IGT) 2-hour glucose 7.8 to 11.0 mmol/liter; and impaired fasting glucose (IFG) 6.1 to 6.9 mmol/liter. Patients known to have DM at the time of transplant listing were termed ‘‘known DM.’’ Patients newly diagnosed with DM by OGTT were termed ‘‘new DM,’’ and those with IGT and/or IFG were termed ‘‘pre-diabetes.’’
Statistics Differences between groups were assessed using the independentsamples Kruskal–Wallis test for ordinal data and chi-square analyses for categorical data. p o 0.05 was considered statistically significant. PASW version 18 (IBM, Armonk, NY) was used for all analyses.
Results Study subjects and incidence of DM Thirty patients were known to have DM. Of the 146 patients who completed the OGTT, 14 had new DM, 29 had prediabetes (1 of whom had isolated IFG), and 103 had normal results (Figure 1). Thus, 44 of the 176 patients assessed for DM prior to transplantation (25.0%) had DM and a further 29 (16.5%) had pre-diabetes. Of the 14 patients with new DM, all had 2-hour glucose Z11.1 mmol/liter, whereas only 2 had fasting plasma glucose Z7.0 mmol/liter. Demographic data of these patients are presented in Table 1.
OGTT and insulin levels in patients not known to have DM
Figure 1
Study subjects.
As expected, there were significant differences in the area under the curve (AUC) for glucose during OGTT (p o 0.001) and HbA1c (p o 0.001) across the 3 groups (DM, pre-diabetes, normal; Table 2). In addition, there was a significant difference between insulin levels at 2 hours
88 Table 1
The Journal of Heart and Lung Transplantation, Vol 32, No 1, January 2013 Patients’ Demographics
Age (years) BMI (kg/m2) Pred (mg)b Taking pred [n (%)] Gender (M/F) (n) Obstructive (n) Restrictive (n) CF/bronch (n) PHT (n) FHx DM
Known DM (n ¼ 30)
New DM (n ¼ 14)
Pre-diabetes (n ¼ 29)
Normal (n ¼ 103)
53 (34–62) 24.0 (21.1–27.8)
59 (50–63) 27.0 (19.5–28.6) 5.0 (0–11.3) 8 (57%) 2/12 7 4 2 1 29%
55 (46–61) 22.2 (19.2–27.2) 0.0 (0–10) 10 (34%) 15/14 13 4 10 2 20%
54 (43–61) 22.7 (20.1–26.3) 0.0 (0–5.0) 38 (38%) 41/62 54 27 16 4 38%
15/15 7 10 12 1 46%
p-valuea across groups 0.46 0.30 0.24 0.32 0.09
0.21
Results are shown as median and interquartile range (IQR). CF, cystic fibrosis; bronch, bronchiectasis; DM, diabetes mellitus; PHT, pulmonary hypertension; pred, prednisolone. a The p-value is given for independent-samples Kruskal Wallis test for age, BMI and prednisolone dose, and for chi-square test for number taking prednisolone, gender and first-degree relative (FHx) with DM. b Prednisolone dose at time of OGTT.
(p o 0.001), but not at baseline or 1 hour. Interestingly, insulin levels remained elevated throughout the OGTT in patients with abnormal glucose tolerance (DM or prediabetes), but fell from 1 to 2 hours in patients with normal glucose tolerance (Figure 2). There were no differences in age, gender, body mass index (BMI), prednisolone dose or family history between the 14 patients who did not complete the OGTT and those whose DM status was assessed, and there were no obvious differences in underlying lung disease.
Insulin resistance and beta-cell function The pathophysiology of abnormal glycemic control was assessed using HOMA. Insulin resistance was higher in those with new DM and pre-diabetes (normal 1.23 [interquartile range 0.76 to 1.73] vs pre-diabetes 1.67 [0.94 to 2.54] vs new DM 1.86 [1.37 to 2.11]; p ¼ 0.029). There was no difference between groups in beta-cell function as assessed by HOMA-B (p ¼ 0.37). Baseline insulin and HOMA-IR were higher in men. Although these were statistically significant (p ¼ 0.031 and Table 2
p ¼ 0.036, respectively), the differences were small and unlikely to be clinically relevant (e.g., median baseline insulin 6.7 mU/liter in men vs 5.5 mU/liter in women). Consistent with the higher fasting insulin levels, there was a trend toward increased beta-cell function in men compared with women (median HOMA-B: 95.0 vs 73.3, respectively; p ¼ 0.056).
Risk factors for pre-transplant dysglycemia Twelve of 14 patients newly diagnosed with DM were women, but a gender difference was not observed in patients with known DM or pre-diabetes and there was no overall gender difference between groups (p ¼ 0.088). There were no significant differences in age, BMI, family history of DM, prednisolone use or prednisolone dose between groups. Fifty-six of 146 patients were taking prednisolone at the time of OGTT. When these patients were excluded to avoid possible bias due to this medication, none of the previously noted risk factors for dysglycemia became significant. In addition, we assessed whether prednisolone use in the 59 patients with BMI 425 kg/m2 in our cohort was
Biochemistry of Patients Who Had OGTT New DM (n ¼ 14)
Glucose 0 h Glucose 1 h Glucose 2 h Glucose AUC Insulin 0 h Insulin 1 h Insulin 2 h Insulin AUC HbA1c HOMA-IR HOMA-B
5.7 12.2 12.0 22.0 7.2 37.4 66.0 78.9 6.0 1.90 63.3
(5.2–6.2) (11.2–15.6) (11.1–16.8) (19.3–25.6) (5.4–8.0) (31.3–51.0) (35.0–123.0) (62.8–123.4) (5.6–6.4) (1.37–2.11) (43.7–105.5)
Pre-diabetes (n ¼ 29) 5.0 (4.7–5.6) 11.0 (9.3–12.3) 8.9 (8.3–9.8) 17.9 (16.1–19.4) 6.8 (4.5–11.2) 54.8 (35.8–99.5) 73.5 (45.0–134.5) 109.9 (61.4–153.1) 6.0 (5.8–6.3) 1.67 (0.94–2.54) 88.4(58.6–152.3)
Normal (n ¼ 103) 4.8 7.7 5.7 12.8 5.6 55.3 33.2 74.0 5.7 1.23 83.8
(4.6–5.2) (6.1–9.0) (4.7–6.6) (11.0–14.5) (3.7–8.0) (37.9–82.3) (20.3–56.0) (54.1–115.4) (5.5–5.9) (0.76–1.73) (55.6–133.3)
p-value across groups o0.001 o0.001 o0.001 o0.001 0.192 0.280 o0.001 0.373 o0.001 0.029 0.374
Results are presented as median (IQR). Glucose measured in millimoles per liter (mmol/liter); insulin measured in milli-units per liter (mU/liter). AUC, area under the curve; HOMA, homeostasis model assessment of insulin resistance (IR) or beta-cell function (B).
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89 sensitivity for detecting pre-diabetes or new DM of 60% and a specificity of 80%. The ADA-suggested level of Z5.7% for the diagnosis of ‘‘pre-diabetes’’ (IGT or IFG) detected 81% of patients with either pre-diabetes or new DM but with a specificity of only 37%.
Discussion
Figure 2 Insulin levels during OGTT in patients with normal glycemia (m), pre-diabetes ( ) and new DM (~). Results are presented as mean ⫾ SEM. p o 0.05 normal vs both prediabetes and new DM.
associated with increased risk of dysglycemia, as the effects of prednisolone use and high BMI may be additive. However, there was no difference in prednisolone use across the groups with dysglycemia and normoglycemia in these patients (p ¼ 0.35). Patient numbers were too small to compare DM status between the 5 categories of underlying lung disease. However, because DM is a known complication of CF, this group was compared against those with non-CF lung disease. As expected, patients with CF were significantly younger (p o 0.001), leaner (p o 0.001) and on lower prednisolone doses (p ¼ 0.011). Patients with CF had a higher prevalence of known DM (36% vs 13%, CF vs others), which probably reflects increased routine screening in these patients. There was no significant difference in newly diagnosed dysglycemia (new DM or pre-diabetes) between patients with CF and nonCF lung disease (24% vs 25%). However, when known DM was taken into account, patients with CF had a higher prevalence of abnormal glycemia (known DM, new DM or IGT) than patients with other diagnoses (61% vs 37%, p ¼ 0.023).
Comparison of HbA1c and OGTT for diagnosis of dysglycemia Using the HbA1c cut-point of Z6.5% suggested for DM diagnosis by the 2009 International Expert Committee report12 and adopted by the American Diabetes Association (ADA),13 the sensitivity for detection of new DM was only 21% with a specificity of 98%. An HbA1c of Z6.0%, the level suggested by the International Expert Committee to diagnose patients at high risk of developing DM,12 had a
This is the first prospective study to examine the prevalence of DM and dysglycemia in patients awaiting lung transplantation and the results are surprising. Using the OGTT in this study to allow definitive diagnosis of DM and detection of pre-diabetes, one quarter of all patients listed for lung transplantation had DM and just under half had either DM or pre-diabetes. Over half of those with abnormal glucose tolerance were newly diagnosed by OGTT. Moreover, no specific risk factors for those with dysglycemia were identified. This high rate of newly diagnosed dysglycemia is significant in a population already closely monitored in tertiary institutions. It is noteworthy that the ‘‘standard’’ tests of fasting glucose and HbA1c were inadequate to diagnose DM and pre-diabetes with sufficient sensitivity. We therefore advocate use of OGTT to screen all waiting list patients, as diagnosis and management prior to transplantation may improve outcomes. Lung recipients have the highest rates of DM after solidorgan transplantation with a 26% prevalence at 5 years and 38% at 10 years.5,7,14,15 Lung recipients also have increased mortality compared with other solid-organ transplant recipients.6,16,17 Hyperglycemia is associated with worse outcomes, including increased mortality and morbidity, in hospitalized patients.18 Although there is no evidence that the high rates of DM in lung transplant recipients are a direct cause, DM is an independent risk factor for 5-year mortality.7 The link may not be mediated by DM-induced vascular damage, as donor history of DM is also a significant risk factor for mortality.19 This raises the possibility that DM may also be associated with nonvascular, small-airway complications in lung transplant recipients. The prevalence of DM in adult Australians is 7.5% with half being unaware of their disease, and a further 16% have pre-diabetes.20 The prevalence of DM is higher in patients with lung disease than in the normal population. Insulindependent DM is present in 21% of adult Australian patients with CF.21 Few studies have assessed the prevalence of DM in obstructive or restrictive lung disease. However, a study of patients aged 440 years with COPD found a 17% prevalence of DM as reported by primary care physicians,22 and COPD has been associated with an increased risk of DM, perhaps via upregulation of inflammatory cytokines.23 There are no data on DM prevalence in patients with restrictive lung disease (RLD), but one study found that these patients had a 1.45-fold increased incidence of DM.24 The 25% prevalence of DM in waiting list patients in the present study was even higher than that in the aforementioned studies, and the prevalence of dysglycemia was almost twice that of the normal population.
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It is difficult to determine whether the prevalence of pretransplant DM is higher in lung transplant recipients than in patients awaiting other solid-organ transplants, because there have been few studies in the latter. Many studies have assessed the prevalence of new DM after transplantation (termed post-transplant diabetes [PTDM]). However, almost all studies of PTDM are retrospective and assessed pretransplant DM by documented use of diabetic medications or clinical notes. This would underestimate the true prevalence of pre-transplant DM and therefore overestimate the rate of PTDM. In the only study of heart transplant patients using the OGTT prior to transplantation, no new cases of diabetes were detected, but IGT was present in 55 of 141 (39%).25 Newly diagnosed DM is also less common in renal transplant patients. Using OGTT, newly diagnosed pre-transplant DM and pre-diabetes were found, respectively, in 15 and 115 of 378 renal transplant patients without known DM.26 Another study that excluded patients with known DM found no new DM but pre-diabetes in 12 of 78 patients who had an OGTT prior to transplantation.27 The last study demonstrated an increased incidence of PTDM in patients with pre-diabetes prior to transplantation, and there was a similar trend in the study of heart transplant patients. No specific risk factors for new DM or pre-diabetes were identified in our study. In contrast to previous studies,20,28–30 age, BMI, prednisolone dose and family history did not appear to influence the risk of dysglycemia. Patients with CF were more likely to have a known diagnosis of DM at the time of listing. This may reflect increased screening for DM, a known complication of CF, in these patients. The lack of obvious risk factors for DM suggests that all patients not known to have DM should be specifically screened prior to transplantation. Only 2 patients had fasting glucose levels in the diabetic range and only 2 had IFG (1 of whom also had IGT), indicating that the OGTT rather than fasting glucose is necessary to make the diagnosis in this population. Patients with diabetes and pre-diabetes had higher HOMA-IR indices as well as higher 2-hour insulin levels, indicating insulin resistance. Although these findings could be consistent with sickness and/or corticosteroid treatment, they are also characteristic of the development of Type 2 DM. Patients in this study were tested either as outpatients or during an elective admission for pre-transplant work-up, so they were not acutely unwell at the time of OGTT. The increased insulin resistance in these patients is therefore most likely to reflect the natural history of the development of DM. The American Diabetes Association (ADA) recently endorsed HbA1c as a diagnostic test for DM, in part because of its ease of accessibility in the general community. A diagnostic level of Z6.5% has been determined as the prevalence of moderate retinopathy begins to rise at this level in the general population.12 However, its 21% sensitivity in this study was too low to advocate its use as a diagnostic test for lung transplant patients. An HbA1c level Z5.7%, the ADA recommendation to determine patients with increased risk of developing DM,13 had a higher sensitivity of 81% but a low specificity of 37% for the diagnosis of dysglycemia.
Further, although HbA1c Z5.7% correlates with the risk of progression to diabetes in the general population, this may not be the case for post-transplant DM in patients awaiting transplantation. The most effective time to educate patients about DM may be prior to transplantation, because, after this procedure, they are often unwell, have multiple medical and allied health teams involved in their care, and may be overwhelmed by the amount of new information they must absorb. In this setting, their ability to learn about and selfmanage DM is more limited and it may be more difficult for diabetes nurse educators to access the patient. One limitation of this study is that patients were not all assessed immediately on transplantation listing. Some patients had been on the waiting list for some time and it is possible that their condition had deteriorated over time, perhaps increasing the risk of dysglycemia. Therefore, we suggest that screening should be repeated regularly after the initial pre-transplant assessment. Also, there were relatively few patients in each category of underlying lung disease, which limited our capacity to determine the relationship between specific diseases and dysglycemia. The high prevalence of DM and IGT in patients awaiting lung transplantation in this study suggests that all patients should be routinely screened for these conditions. An OGTT should be used because HbA1c and fasting glucose lack the required sensitivity and specificity in this population. In patients with pre-diabetes, further studies are required to determine the rate of progression to diabetes and whether it increases morbidity pre-transplant and the development of post-transplant DM. Detection of DM prior to transplantation would allow for early patient education and management and potentially a better outcome while still on the waiting list. It would also minimize the risk of acute hyperglycemia and, given the association of DM with increased post-transplant morbidity and mortality, early detection and management may improve these outcomes. Further studies of the clinical consequences of pre-transplant dysglycemia are therefore required.
Disclosure statement K.L.H. received a Monash Faculty Postgraduate Scholarship and an Alfred Research Trusts Postgraduate Scholarship. The other authors have no conflicts of interest to disclose. We thank Melissa Vereker (The Alfred Hospital, Melbourne) for help with the creation and modification of a patient database.
References 1. Wilkinson A, Davidson J, Dotta F, et al. Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin Transplant 2005;19:291-8. 2. Baid S, Cosimi AB, Farrell ML, et al. Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality. Transplantation 2001;72:1066-72. 3. Hjelmesaeth J, Hartmann A, Kofstad J, et al. Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation 1997;64:979-83.
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4. van Hooff JP, Christiaans MH, van Duijnhoven EM. Evaluating mechanisms of post-transplant diabetes mellitus. Nephrol Dial Transplant 200419(suppl 6):vi8-12. 5. Depczynski B, Daly B, Campbell LV, et al. Predicting the occurrence of diabetes mellitus in recipients of heart transplants. Diabet Med 2000;17:15-9. 6. Australia and New Zealand Cardiothoracic Organ Transplant Registry fifteenth annual report 2010, 2010. Available from: http://www. anzcotr.org.au/uploadedFiles/1279001464281-56522.pdf. Access October 16, 2011. 7. Christie JD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung transplantation: twentyseventh official adult lung and heart–ung transplant report–2010. J Heart Lung Transplant 2010;29:1104-18. 8. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update–a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745-55. 9. Sacks DB, Arnold M, Bakris GL, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care 2011;34:e61-99. 10. Matthews D, Hosker J, Rudenski A, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9. 11. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation., 2006. Available from: http://whqlibdoc.who.int/publications/2006/9241594934_eng.pdf. Access October 16, 2011. 12. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327-34. 13. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33(suppl 1):S62-9. 14. Bigam DL, Pennington JJ, Carpentier A, et al. Hepatitis C-related cirrhosis: a predictor of diabetes after liver transplantation. Hepatology 2000;32:87-90. 15. Cosio FG, Pesavento TE, Osei K, et al. Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int 2001;59:732-7. 16. ANZDATA 33rd annual report, 2010. Available from: http://www. anzdata.org.au/anzdata/AnzdataReport/33rdReport/Ch08.pdf. Access October 16, 2011. 17. ANZLT Registry Report 2010, 2011. Available from: http://www. anzltr.org/thisYear/report.pdf. Access October 16, 2011.
91 18. Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control. Diabetes Care 2009;32:1119-31. 19. Christie JD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: twentyseventh official adult lung and heart–lung transplant report—2010. J Heart Lung Transplant 2010;29:1104-18. 20. Dunstan DW, Zimmet PZ, Welborn TA, et al. The rising prevalence of diabetes and impaired glucose tolerance. Diabetes Care 2002;25:829. 21. Bell SC, Bye PT, Cooper PJ, et al. Cystic fibrosis in Australia, 2009: results from a data registry. Med J Aust 2011;195:396-400. 22. Jimenez-Garcia R, de Miguel-Diez J, Rejas-Gutierrez J, et al. Health, treatment and health care resources consumption profile among Spanish adults with diabetes and chronic obstructive pulmonary disease. Primary Care Diabetes 2009;3:141-8. 23. Rana JS, Mittleman MA, Sheikh J, et al. Chronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in women. Diabetes Care 2004;27:2478-84. 24. Ford ES, Mannino DM. National Health Nutrition Examination Survey Epidemiologic Follow-up Study. Prospective association between lung function and the incidence of diabetes: findings from the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Diabetes Care 2004;27:2966-70. 25. Nieuwenhuis MG, Kirkels JH. Predictability and other aspects of posttransplant diabetes mellitus in heart transplant recipients. J Heart Lung Transplant 2001;20:703-8. 26. Iida S, Ishida H, Tokumoto T, et al. New-onset diabetes after transplantation in tacrolimus-treated, living kidney transplantation: long-term impact and utility of the pre-transplant OGTT. Int Urol Nephrol 2010;42:935-45. 27. Ramesh Prasad GV, Huang M, Bandukwala F, et al. Pre-transplantation glucose testing for predicting new-onset diabetes mellitus after renal transplantation. Clin Nephrol 2009;71:140-6. 28. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Kronenberg HM, Melmed S, Polonsky KS, editors. Williams textbook of endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 2008. p. 1329-36. 29. Donihi AC, Raval D, Saul M, et al. Prevalence and predictors of corticosteroid-related hyperglycemia in hospitalized patients. Endocrine Pract 2006;12:358-62. 30. Burt MG, Roberts GW, Aguilar-Loza NR, et al. Continuous monitoring of circadian glycemic patterns in patients receiving prednisolone for COPD. J Clin Endocrinol Metabol 2011;96:1789-96.
ORIGINAL CLINICAL SCIENCE
An unexpectedly high prevalence of undiagnosed diabetes in patients awaiting lung transplantation Kathryn L. Hackman, MBBS, FRACP,a,b Gregory I. Snell, MBBS, PhD, FRACP,b,c and Leon A. Bach, MBBS, PhD, FRACPa,b From the aDepartment of Endocrinology and Diabetes, The Alfred Hospital, Melbourne; bDepartment of Medicine (Alfred), Monash University, Melbourne; and the cLung Transplant Service, The Alfred Hospital, Melbourne, Victoria, Australia.
KEYWORDS: lung transplantation; diabetes mellitus; prevalence; oral glucose tolerance test
BACKGROUND: Diabetes mellitus (DM) is a common complication after lung transplantation but its prevalence prior to transplantation has not been determined. We sought to determine the prevalence of and risk factors for DM in adults awaiting lung transplantation and to determine whether pre-transplant DM could be diagnosed by hemoglobin A1c (HbA1c) alone. METHODS: All patients wait-listed for lung transplantation over a 2-year period had HbA1c measured. Those not known to have DM also underwent an oral glucose tolerance test (OGTT) with insulin levels. RESULTS: Of 190 patients listed for lung transplantation, 30 (16%) had been diagnosed previously with DM. Twelve patients received transplants and 1 came off the waiting list before having an OGTT. The remaining patients underwent OGTT: 14 were newly diagnosed with DM and 29 with pre-diabetes. One patient vomited during the test and was excluded from analyses. Thus, 41% of all screened waiting list patients had DM (known or newly diagnosed) or pre-diabetes. Neither age, BMI, prednisolone dose nor family history correlated with dysglycemia. Patients with newly diagnosed DM and pre-diabetes were more insulin-resistant than those with normoglycemia. HbA1c correlated poorly with OGTT. CONCLUSIONS: Patients awaiting lung transplantation have unexpectedly high rates of DM and prediabetes despite close medical follow-up. Screening for DM with an OGTT will allow early intervention, which may improve outcomes after transplantation. J Heart Lung Transplant 2013;32:86–91 r 2013 International Society for Heart and Lung Transplantation. All rights reserved.
Few studies have prospectively assessed the incidence of diabetes mellitus (DM) prior to transplantation and none have prospectively assessed its incidence in patients awaiting lung transplantation. The high incidence of DM after solid-organ transplantation is generally assumed to be of new onset, occurring as a complication of immunosuppressive agents including glucocorticoids and calcineurin inhibitors.1–5 The annual number of lung transplantation procedures performed in Australia6 and worldwide7 has increased significantly over the past decade. Although life expectancy Reprint requests: Leon A. Bach, MBBS, PhD, FRACP, Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne 3004, Victoria, Australia. Telephone þ61-3-9076-2460. Fax: þ61-3-9076-3782. E-mail address: [email protected]
has improved in recent years, it is still lower than that of other solid-organ transplants. Diabetes is a significant risk factor for mortality at both 1 and 5 years after lung transplantation,7 and lung transplant recipients have a particularly high incidence of post-transplant DM as they require prolonged, high-dose treatment with diabetogenic immunosuppressants. However, these patients may already be at increased risk of DM prior to transplantation. For example, patients awaiting transplantation due to chronic obstructive lung disease (COPD) may already be taking glucocorticoids, whereas patients with cystic fibrosis (CF) may have impaired pancreatic endocrine function. Many units assess patients for diabetes with a fasting or random blood glucose level or hemoglobin A1c (HbA1c)
1053-2498/$ - see front matter r 2013 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2012.10.010
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test. These tests are quick and simple. However, the current gold standard for DM diagnosis is the oral glucose tolerance test (OGTT). Not only does it have a higher sensitivity than HbA1c for detecting DM, it is the only way to diagnose impaired glucose tolerance, which is associated with an increased risk of diabetes and cardiovascular disease. The OGTT may be used less frequently as it takes 2 hours and requires several blood samples. In this study we aimed to determine the prevalence of abnormal glycemic control (DM, impaired glucose tolerance or impaired fasting glucose) and the risk factors for dysglycemia in patients awaiting lung transplantation. We also assessed whether the diagnosis of DM could be simplified with the use of a single, non-fasting blood test—the HbA1c—rather than the standard OGTT.
87 although some patients were tested at their local pathology service. Prednisolone dose was recorded at the time of OGTT. Patients were asked about family history of diabetes. The homeostasis model assessments of insulin resistance (HOMA-IR) and beta-cell function (HOMA-B) were calculated from baseline fasting glucose and insulin levels on the OGTT. The simplified HOMA equations10 for insulin resistance and beta-cell function, where FPI is fasting plasma insulin concentration (mU/ liter) and FPG is fasting plasma glucose (mmol/liter), were used: HOMA-IR¼ ðFPI FPGÞ=22:5 HOMA-Bð%Þ ¼ ð20 FPIÞ=ðFPG-3:5Þ Glucose was measured by the hexokinase method and insulin by the chemiluminescent microparticle-enhanced immunoassay (CMIA) on an Abbott Architect ci16 200 (Abbott Diagnostics, Abbott Park, IL). HbA1c was measured by boronate affinity highperformance liquid chromatography (CLC 330; Primus Diagnostics, Kansas City, MO).
Methods Definitions Patients All patients aged 418 years (n ¼ 190), who were on the waiting list for lung transplantation at The Alfred Hospital, Melbourne, from August 1, 2010 to July 31, 2012 and who had not received a prior solid-organ transplant, were evaluated for DM. Patients were placed on the waiting list according to international guidelines for recipient suitability.8 Twelve patients who proceeded to transplantation, 1 who withdrew from the waiting list before OGTT and 1 who vomited during the OGTT were excluded from subsequent analyses (Figure 1). Patient demographics and underlying diagnoses were obtained from medical records. The study was reviewed and approved by the ethics committee of The Alfred Hospital.
Approach to study To determine pre-transplant diabetes status, all patients not known to have DM underwent a standard 2-hour 75-g OGTT after an overnight fast. Insulin levels were measured on each blood sample (0, 1 hour and 2 hours). The HbA1c, standardized to the Diabetes Control and Complications Trial (DCCT) assay,9 was also measured. Most tests were performed at The Alfred Hospital,
The 2006 World Health Organization criteria11 were used to diagnose DM, venous fasting plasma glucose Z7.0 mmol/liter or 2hour glucose Z11.1 mmol/liter; impaired glucose tolerance (IGT) 2-hour glucose 7.8 to 11.0 mmol/liter; and impaired fasting glucose (IFG) 6.1 to 6.9 mmol/liter. Patients known to have DM at the time of transplant listing were termed ‘‘known DM.’’ Patients newly diagnosed with DM by OGTT were termed ‘‘new DM,’’ and those with IGT and/or IFG were termed ‘‘pre-diabetes.’’
Statistics Differences between groups were assessed using the independentsamples Kruskal–Wallis test for ordinal data and chi-square analyses for categorical data. p o 0.05 was considered statistically significant. PASW version 18 (IBM, Armonk, NY) was used for all analyses.
Results Study subjects and incidence of DM Thirty patients were known to have DM. Of the 146 patients who completed the OGTT, 14 had new DM, 29 had prediabetes (1 of whom had isolated IFG), and 103 had normal results (Figure 1). Thus, 44 of the 176 patients assessed for DM prior to transplantation (25.0%) had DM and a further 29 (16.5%) had pre-diabetes. Of the 14 patients with new DM, all had 2-hour glucose Z11.1 mmol/liter, whereas only 2 had fasting plasma glucose Z7.0 mmol/liter. Demographic data of these patients are presented in Table 1.
OGTT and insulin levels in patients not known to have DM
Figure 1
Study subjects.
As expected, there were significant differences in the area under the curve (AUC) for glucose during OGTT (p o 0.001) and HbA1c (p o 0.001) across the 3 groups (DM, pre-diabetes, normal; Table 2). In addition, there was a significant difference between insulin levels at 2 hours
88 Table 1
The Journal of Heart and Lung Transplantation, Vol 32, No 1, January 2013 Patients’ Demographics
Age (years) BMI (kg/m2) Pred (mg)b Taking pred [n (%)] Gender (M/F) (n) Obstructive (n) Restrictive (n) CF/bronch (n) PHT (n) FHx DM
Known DM (n ¼ 30)
New DM (n ¼ 14)
Pre-diabetes (n ¼ 29)
Normal (n ¼ 103)
53 (34–62) 24.0 (21.1–27.8)
59 (50–63) 27.0 (19.5–28.6) 5.0 (0–11.3) 8 (57%) 2/12 7 4 2 1 29%
55 (46–61) 22.2 (19.2–27.2) 0.0 (0–10) 10 (34%) 15/14 13 4 10 2 20%
54 (43–61) 22.7 (20.1–26.3) 0.0 (0–5.0) 38 (38%) 41/62 54 27 16 4 38%
15/15 7 10 12 1 46%
p-valuea across groups 0.46 0.30 0.24 0.32 0.09
0.21
Results are shown as median and interquartile range (IQR). CF, cystic fibrosis; bronch, bronchiectasis; DM, diabetes mellitus; PHT, pulmonary hypertension; pred, prednisolone. a The p-value is given for independent-samples Kruskal Wallis test for age, BMI and prednisolone dose, and for chi-square test for number taking prednisolone, gender and first-degree relative (FHx) with DM. b Prednisolone dose at time of OGTT.
(p o 0.001), but not at baseline or 1 hour. Interestingly, insulin levels remained elevated throughout the OGTT in patients with abnormal glucose tolerance (DM or prediabetes), but fell from 1 to 2 hours in patients with normal glucose tolerance (Figure 2). There were no differences in age, gender, body mass index (BMI), prednisolone dose or family history between the 14 patients who did not complete the OGTT and those whose DM status was assessed, and there were no obvious differences in underlying lung disease.
Insulin resistance and beta-cell function The pathophysiology of abnormal glycemic control was assessed using HOMA. Insulin resistance was higher in those with new DM and pre-diabetes (normal 1.23 [interquartile range 0.76 to 1.73] vs pre-diabetes 1.67 [0.94 to 2.54] vs new DM 1.86 [1.37 to 2.11]; p ¼ 0.029). There was no difference between groups in beta-cell function as assessed by HOMA-B (p ¼ 0.37). Baseline insulin and HOMA-IR were higher in men. Although these were statistically significant (p ¼ 0.031 and Table 2
p ¼ 0.036, respectively), the differences were small and unlikely to be clinically relevant (e.g., median baseline insulin 6.7 mU/liter in men vs 5.5 mU/liter in women). Consistent with the higher fasting insulin levels, there was a trend toward increased beta-cell function in men compared with women (median HOMA-B: 95.0 vs 73.3, respectively; p ¼ 0.056).
Risk factors for pre-transplant dysglycemia Twelve of 14 patients newly diagnosed with DM were women, but a gender difference was not observed in patients with known DM or pre-diabetes and there was no overall gender difference between groups (p ¼ 0.088). There were no significant differences in age, BMI, family history of DM, prednisolone use or prednisolone dose between groups. Fifty-six of 146 patients were taking prednisolone at the time of OGTT. When these patients were excluded to avoid possible bias due to this medication, none of the previously noted risk factors for dysglycemia became significant. In addition, we assessed whether prednisolone use in the 59 patients with BMI 425 kg/m2 in our cohort was
Biochemistry of Patients Who Had OGTT New DM (n ¼ 14)
Glucose 0 h Glucose 1 h Glucose 2 h Glucose AUC Insulin 0 h Insulin 1 h Insulin 2 h Insulin AUC HbA1c HOMA-IR HOMA-B
5.7 12.2 12.0 22.0 7.2 37.4 66.0 78.9 6.0 1.90 63.3
(5.2–6.2) (11.2–15.6) (11.1–16.8) (19.3–25.6) (5.4–8.0) (31.3–51.0) (35.0–123.0) (62.8–123.4) (5.6–6.4) (1.37–2.11) (43.7–105.5)
Pre-diabetes (n ¼ 29) 5.0 (4.7–5.6) 11.0 (9.3–12.3) 8.9 (8.3–9.8) 17.9 (16.1–19.4) 6.8 (4.5–11.2) 54.8 (35.8–99.5) 73.5 (45.0–134.5) 109.9 (61.4–153.1) 6.0 (5.8–6.3) 1.67 (0.94–2.54) 88.4(58.6–152.3)
Normal (n ¼ 103) 4.8 7.7 5.7 12.8 5.6 55.3 33.2 74.0 5.7 1.23 83.8
(4.6–5.2) (6.1–9.0) (4.7–6.6) (11.0–14.5) (3.7–8.0) (37.9–82.3) (20.3–56.0) (54.1–115.4) (5.5–5.9) (0.76–1.73) (55.6–133.3)
p-value across groups o0.001 o0.001 o0.001 o0.001 0.192 0.280 o0.001 0.373 o0.001 0.029 0.374
Results are presented as median (IQR). Glucose measured in millimoles per liter (mmol/liter); insulin measured in milli-units per liter (mU/liter). AUC, area under the curve; HOMA, homeostasis model assessment of insulin resistance (IR) or beta-cell function (B).
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89 sensitivity for detecting pre-diabetes or new DM of 60% and a specificity of 80%. The ADA-suggested level of Z5.7% for the diagnosis of ‘‘pre-diabetes’’ (IGT or IFG) detected 81% of patients with either pre-diabetes or new DM but with a specificity of only 37%.
Discussion
Figure 2 Insulin levels during OGTT in patients with normal glycemia (m), pre-diabetes ( ) and new DM (~). Results are presented as mean ⫾ SEM. p o 0.05 normal vs both prediabetes and new DM.
associated with increased risk of dysglycemia, as the effects of prednisolone use and high BMI may be additive. However, there was no difference in prednisolone use across the groups with dysglycemia and normoglycemia in these patients (p ¼ 0.35). Patient numbers were too small to compare DM status between the 5 categories of underlying lung disease. However, because DM is a known complication of CF, this group was compared against those with non-CF lung disease. As expected, patients with CF were significantly younger (p o 0.001), leaner (p o 0.001) and on lower prednisolone doses (p ¼ 0.011). Patients with CF had a higher prevalence of known DM (36% vs 13%, CF vs others), which probably reflects increased routine screening in these patients. There was no significant difference in newly diagnosed dysglycemia (new DM or pre-diabetes) between patients with CF and nonCF lung disease (24% vs 25%). However, when known DM was taken into account, patients with CF had a higher prevalence of abnormal glycemia (known DM, new DM or IGT) than patients with other diagnoses (61% vs 37%, p ¼ 0.023).
Comparison of HbA1c and OGTT for diagnosis of dysglycemia Using the HbA1c cut-point of Z6.5% suggested for DM diagnosis by the 2009 International Expert Committee report12 and adopted by the American Diabetes Association (ADA),13 the sensitivity for detection of new DM was only 21% with a specificity of 98%. An HbA1c of Z6.0%, the level suggested by the International Expert Committee to diagnose patients at high risk of developing DM,12 had a
This is the first prospective study to examine the prevalence of DM and dysglycemia in patients awaiting lung transplantation and the results are surprising. Using the OGTT in this study to allow definitive diagnosis of DM and detection of pre-diabetes, one quarter of all patients listed for lung transplantation had DM and just under half had either DM or pre-diabetes. Over half of those with abnormal glucose tolerance were newly diagnosed by OGTT. Moreover, no specific risk factors for those with dysglycemia were identified. This high rate of newly diagnosed dysglycemia is significant in a population already closely monitored in tertiary institutions. It is noteworthy that the ‘‘standard’’ tests of fasting glucose and HbA1c were inadequate to diagnose DM and pre-diabetes with sufficient sensitivity. We therefore advocate use of OGTT to screen all waiting list patients, as diagnosis and management prior to transplantation may improve outcomes. Lung recipients have the highest rates of DM after solidorgan transplantation with a 26% prevalence at 5 years and 38% at 10 years.5,7,14,15 Lung recipients also have increased mortality compared with other solid-organ transplant recipients.6,16,17 Hyperglycemia is associated with worse outcomes, including increased mortality and morbidity, in hospitalized patients.18 Although there is no evidence that the high rates of DM in lung transplant recipients are a direct cause, DM is an independent risk factor for 5-year mortality.7 The link may not be mediated by DM-induced vascular damage, as donor history of DM is also a significant risk factor for mortality.19 This raises the possibility that DM may also be associated with nonvascular, small-airway complications in lung transplant recipients. The prevalence of DM in adult Australians is 7.5% with half being unaware of their disease, and a further 16% have pre-diabetes.20 The prevalence of DM is higher in patients with lung disease than in the normal population. Insulindependent DM is present in 21% of adult Australian patients with CF.21 Few studies have assessed the prevalence of DM in obstructive or restrictive lung disease. However, a study of patients aged 440 years with COPD found a 17% prevalence of DM as reported by primary care physicians,22 and COPD has been associated with an increased risk of DM, perhaps via upregulation of inflammatory cytokines.23 There are no data on DM prevalence in patients with restrictive lung disease (RLD), but one study found that these patients had a 1.45-fold increased incidence of DM.24 The 25% prevalence of DM in waiting list patients in the present study was even higher than that in the aforementioned studies, and the prevalence of dysglycemia was almost twice that of the normal population.
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It is difficult to determine whether the prevalence of pretransplant DM is higher in lung transplant recipients than in patients awaiting other solid-organ transplants, because there have been few studies in the latter. Many studies have assessed the prevalence of new DM after transplantation (termed post-transplant diabetes [PTDM]). However, almost all studies of PTDM are retrospective and assessed pretransplant DM by documented use of diabetic medications or clinical notes. This would underestimate the true prevalence of pre-transplant DM and therefore overestimate the rate of PTDM. In the only study of heart transplant patients using the OGTT prior to transplantation, no new cases of diabetes were detected, but IGT was present in 55 of 141 (39%).25 Newly diagnosed DM is also less common in renal transplant patients. Using OGTT, newly diagnosed pre-transplant DM and pre-diabetes were found, respectively, in 15 and 115 of 378 renal transplant patients without known DM.26 Another study that excluded patients with known DM found no new DM but pre-diabetes in 12 of 78 patients who had an OGTT prior to transplantation.27 The last study demonstrated an increased incidence of PTDM in patients with pre-diabetes prior to transplantation, and there was a similar trend in the study of heart transplant patients. No specific risk factors for new DM or pre-diabetes were identified in our study. In contrast to previous studies,20,28–30 age, BMI, prednisolone dose and family history did not appear to influence the risk of dysglycemia. Patients with CF were more likely to have a known diagnosis of DM at the time of listing. This may reflect increased screening for DM, a known complication of CF, in these patients. The lack of obvious risk factors for DM suggests that all patients not known to have DM should be specifically screened prior to transplantation. Only 2 patients had fasting glucose levels in the diabetic range and only 2 had IFG (1 of whom also had IGT), indicating that the OGTT rather than fasting glucose is necessary to make the diagnosis in this population. Patients with diabetes and pre-diabetes had higher HOMA-IR indices as well as higher 2-hour insulin levels, indicating insulin resistance. Although these findings could be consistent with sickness and/or corticosteroid treatment, they are also characteristic of the development of Type 2 DM. Patients in this study were tested either as outpatients or during an elective admission for pre-transplant work-up, so they were not acutely unwell at the time of OGTT. The increased insulin resistance in these patients is therefore most likely to reflect the natural history of the development of DM. The American Diabetes Association (ADA) recently endorsed HbA1c as a diagnostic test for DM, in part because of its ease of accessibility in the general community. A diagnostic level of Z6.5% has been determined as the prevalence of moderate retinopathy begins to rise at this level in the general population.12 However, its 21% sensitivity in this study was too low to advocate its use as a diagnostic test for lung transplant patients. An HbA1c level Z5.7%, the ADA recommendation to determine patients with increased risk of developing DM,13 had a higher sensitivity of 81% but a low specificity of 37% for the diagnosis of dysglycemia.
Further, although HbA1c Z5.7% correlates with the risk of progression to diabetes in the general population, this may not be the case for post-transplant DM in patients awaiting transplantation. The most effective time to educate patients about DM may be prior to transplantation, because, after this procedure, they are often unwell, have multiple medical and allied health teams involved in their care, and may be overwhelmed by the amount of new information they must absorb. In this setting, their ability to learn about and selfmanage DM is more limited and it may be more difficult for diabetes nurse educators to access the patient. One limitation of this study is that patients were not all assessed immediately on transplantation listing. Some patients had been on the waiting list for some time and it is possible that their condition had deteriorated over time, perhaps increasing the risk of dysglycemia. Therefore, we suggest that screening should be repeated regularly after the initial pre-transplant assessment. Also, there were relatively few patients in each category of underlying lung disease, which limited our capacity to determine the relationship between specific diseases and dysglycemia. The high prevalence of DM and IGT in patients awaiting lung transplantation in this study suggests that all patients should be routinely screened for these conditions. An OGTT should be used because HbA1c and fasting glucose lack the required sensitivity and specificity in this population. In patients with pre-diabetes, further studies are required to determine the rate of progression to diabetes and whether it increases morbidity pre-transplant and the development of post-transplant DM. Detection of DM prior to transplantation would allow for early patient education and management and potentially a better outcome while still on the waiting list. It would also minimize the risk of acute hyperglycemia and, given the association of DM with increased post-transplant morbidity and mortality, early detection and management may improve these outcomes. Further studies of the clinical consequences of pre-transplant dysglycemia are therefore required.
Disclosure statement K.L.H. received a Monash Faculty Postgraduate Scholarship and an Alfred Research Trusts Postgraduate Scholarship. The other authors have no conflicts of interest to disclose. We thank Melissa Vereker (The Alfred Hospital, Melbourne) for help with the creation and modification of a patient database.
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