Review Articles

Resistance to epidermal growth factor receptor inhibitors in non-small cell lung cancer and strategies to overcome it

The War on Cancer has been a particularly long, drawn-out one ever since the National Cancer Act was put into legislation by then U.S. President Richard Nixon. While we attempt to reveal the mechanisms that sustain the uncontrolled growth of cancer cells, the biology of cancer constantly changes and adapts to evade our treatment modalities. The discovery of imatinib, which is a tyrosine kinase inhibitor (TKI) and treats a subset of chronic myelogenous leukaemia, heralded a new generation of drugs that would specifically target cancer cells and reduce toxicity to normal cells. Erlotinib and gefitinib are two epidermal growth factor receptor (EGFR) TKI’s that have been developed for the treatment of patients with EGFR-mutation-expressing non-small cell lung carcinoma. However, in recent years, resistance to EGFR TKIs has been described in the literature. While the promise of a new treatment modality has been short-lived, this has also sparked interest and research efforts to understand the mechanisms of resistance to EGFR TKIs in a bid to discover strategies to overcome them and to further drug development. Well studied mechanisms include T790M mutation, loss of balance in the PI3K/Akt/mTOR pathway and MET amplification amongst many others. This article reviews the current literature regarding various mechanisms of resistance to EGFR TKIs and their potential for translation into new therapeutic agents and treatment strategies.


Resistance to epidermal growth factor receptor inhibitors in non-small cell lung cancer and strategies to overcome itOne famous discovery of a targeted drug treatment is imatinib, a tyrosine kinase inhibitor (TKI) used to treat a subset of chronic myelogenous leukaemia expressing the Philadelphia chromosome. This discovery has triggered a series of research efforts, shedding light on topics such as tumourigenesis and cell signaling pathways, leading to the development of many new drugs which target these specific mechanisms. However, it has been documented that resistance to these drugs can develop, therefore reducing their treatment potential [1,2] This is also true for a similar group of TKIs known as epidermal growth factor receptor (EGFR) inhibitors, which have been used as part of the treatment regime for a subgroup of lung cancer patients with non-small cell lung carcinoma. This article will review the mechanisms of intrinsic and acquired resistance to EGFR inhibitors and strategies to overcome them.

Introduction to EGFR inhibitors

The work of Stanley Cohen and Rita Levi-Montalcini in Epidermal Growth Factors has revolutionized cancer research and treatment, having been awarded the 1986 Nobel Prize for Medicine. [3] Their work has triggered further research, eventuating into the approval of gefitinib in 2003 and erlotinib in 2010 by the Food and Drug Administration (FDA) for use in patients with NSCLC. [4-6]

The overexpression and over-activation of EGFR (independent of any ligands) has been found to be involved in the tumour progression of many different types of cancers. [7] Aberrant activation of this oncogene leads to a cascade of complex downstream signaling that contributes to tumourigenesis. [8] The understanding of EGFR’s role in tumourigenesis assisted in the development of gefitinib and erlotinib as first generation TKIs to target and block EGFR activity to retard cancer growth. They bind reversibly to the ATP binding pocket of EGFR, preventing receptor phosphorylation and subsequent downstream intracellular signaling. [6,8] There is evidence to suggest that EGFR TKIs have led to significant extension of progression-free survival as a second or third line treatment in patients with advanced NSCLC with positive EGFR status. [6,9,10] Promising results have also emerged in recent years for the use of EGFR TKIs as first line treatment for NSCLC patients exhibiting EGFR mutations in Phase III trials. [10-13]
Lung cancer is the 5th most commonly diagnosed cancer in Australia with poor 5-year survival rates of around 14%. [14] Specifically, NSCLC accounts for 60% of all cases of lung cancer. [15] According to the guidelines for lung cancer treatment in Australia, the role of EGFR TKIs (erlotinib), remains primarily in the treatment of Stage IV inoperable NSCLC. [16] It is not recommended for first-generation EGFR TKIs like gefitinib or erlotinib to be used in combination with standard chemotherapy regimens. Erlotinib plays more of a role as a first-line maintenance therapy after standard chemotherapy, as a second-line therapy instead of chemotherapy or as a third-line therapy after having failed two lines of treatment and for patients with poor performance status.
In 2010, Jackman et al. proposed a definition of acquired resistance to EGFR inhibitors to help standardize investigations into this topic. [17] They have found that about 70% of NSCLC patients with positive EGFR mutation status will experience tumour regressions whilst on either gefitinib or erlotinib. However, most initial responders develop acquired resistance to EGFR TKIs, [6] usually occurring about after 12 months of treatment. [18,19] Therefore, much effort has been dedicated to understanding and rediscovering the different mechanisms of EGFR inhibitor resistance-both intrinsic and acquired-in order to develop strategies to overcome them.

Areas of interest

There are numerous hypotheses as to how NSCLC patients develop resistance to EGFR TKIs. However, mechanisms of EGFR TKI resistance that have been more extensively studied and show the most potential for translation into clinical practice will be highlighted in this article.

T790M – The ‘gatekeeper mutation’

The mechanism of resistance that is most commonly identified in recent work is an acquired mutation in the EGFR gene at position 790 (T790M) in exon 20. This involves a threonine to methionine substitution and it is present in 50% of patients with acquired resistance to EGFR TKIs. [6,7,9,20] This substitution mutation causes steric interference with the binding of EGFR TKIs to the ATP binding site. [21] It is also hypothesized that this mutation leads to increased ATP affinity, conferring drug resistance. [6,21] This allows for phosphorylation of EGFR despite the administration of TKIs due to its restored affinity for ATP, allowing the cancer cell to grow unchecked once again with the restoration of EGFR activation. Of interest, some studies have found T790M mutations occurring at low frequency in the germ line of TKI-naive patients, [6,22,23] indicating potential intrinsic resistance. This mutation can also be found in NSCLC patients expressing wild-type EGFR before treatment, possibly explaining that the T790M mutation may be a contributing factor to intrinsic resistance to TKIs. [7]

Figure 1. T790M driven drug resistance and mechanism of action of different generations of EGFR TKIs.
Figure 1. T790M driven drug resistance and mechanism of action of different generations of EGFR TKIs.

Loss of PTEN expression and PIK3CA mutation in the PI3K/Akt/mTOR pathway

A complex network of signaling pathways interacting via various molecules are involved in cancer cell growth independent of EGFR activity. These signaling pathways are usually downstream of an EGFR and can potentially bypass loss of EGFR activation due to administration of TKIs such as gefitinib and erlotinib. One important pathway is the PI3K/Akt/mTOR signaling pathway. Sustained activation of Akt can potentiate resistance to chemotherapy and radiotherapy in general. [24,25] For EGFR-expressing NSCLC patients, Akt is strongly activated to maintain the survival of cancer cells. Activation of Akt always involves membrane recruitment for phosphate transfer. This is regulated positively by phosphoinositol-3-kinase (PI3K) and negatively by phosphatase and tensin homologue (PTEN), a tumour suppressor gene product. Therefore, loss of PTEN expression, via a deletion on chromosome 10, leads to uncontrolled phosphate transfer and activation of Akt, which is commonly observed in NSCLC patients with EGFR TKI resistance. [7,26] On the other hand, a PI3K catalytic alpha (PIK3CA) oncogene mutation is also observed in a small minority of advanced NSCLC patients. [27] This mutation enhances the positive regulation of the pathway via PI3K, thereby leading to heightened activation of Akt. As it is noted that PIK3CA mutations are commonly found in treatment naive lung adenocarcinoma [6] with concurrent driver mutations in EGFR, KRAS or BRAF, PIK3CA mutation is likely to be a secondary, acquired mutation contributing to resistance. [28] By targeting these mechanisms, a patient’s response to EGFR TKIs can potentially be restored.

Insulin-like growth factor 1 Receptor – Parallel EGFR independent pathway

Like EGFR, Insulin-like growth factor 1 receptor (IGF-1R) is a tyrosine kinase that can trigger similar downstream signaling events. Blockade of EGFR pathways with TKI administration has led to compensatory or adaptive upregulation of downstream signaling via the IGF-1R pathway which eventually leads to sustained activation of the PI3K/Akt/mTOR pathway. [29] Gefitinib-resistant cancer cells are also found to have reduced expression of IGF binding proteins, [8] which modulates the activity of IGF-1R by binding to IGF ligands such as IGF-1 and IGF-2. Loss of these binding proteins leads to higher levels of IGF-1 and IGF-2, which increases constitutive activation of the IGF-1R tyrosine kinase and its downstream targets.

Figure 2. PI3K/Akt/mTOR pathway.
Figure 2. PI3K/Akt/mTOR pathway.

MET pathway amplification

EGFR is an important member of a class of four ErbB receptor tyrosine kinases – EGFR/HER1/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4. Dimerization of any two of this class of receptors (homodimerization or heterodimerization) will lead to phosphorylation and eventual downstream signal cascade. MET (Mesenchymal- Epithelial Transition) is a receptor tyrosine kinase that binds to hepatocyte growth factor (HGF) and is found to undergo amplification in the presence of TKIs. The extensive crosstalk between the HGF/ MET pathway and the PI3K/Akt/mTOR pathway strongly reactivates downstream signals through HER3/ErbB3 phosphorylation, resulting in similar downstream events as EGFR phosphorylation, despite TKI administration. [6,9,18,30] Another interesting observation is that both MET and EGFR have loci on chromosome 7 and EGFR mutation positive NSCLC patients commonly have polysomy of chromosome 7. [19,31] This could be a contributing factor to the presence of intrinsic resistance to EGFR TKIs as targeting EGFRs does not negate the effect of co-existing MET amplification on the PI3K/Akt pathway.

Figure 3. MET amplification.
Figure 3. MET amplification.


The vascular endothelial growth factor (VEGF) pathway, which plays a key role in angiogenesis, is another signaling pathway that can be targeted. This is based on the principle that multiple oncogenic targets can contribute to the malignant phenotype. By targeting multiple oncogenic targets, such as inhibition of both EGFR and VEGF, it is hoped that this would circumvent development of resistance to EGFR TKIs, maintaining treatment efficacy. [32]

Sequist et al. observed that a histological transformation from NSCLC to small cell lung cancer (SCLC) can occur with TKI treatment. [33] This was found in 14% of EGFR-expressing NSCLC patients who have acquired EGFR TKI resistance. The significance of this is that the histological transformation has now given the patient a chance of a good response with standard SCLC chemotherapy regimens. More investigations regarding this are necessary to understand the mechanism of the transformation as it can potentially be a novel strategy for the treatment of NSCLC patients.

Novel Therapies being investigated to overcome EGFR TKI resistance

2nd Generation Irreversible Tyrosine Kinase Inhibitors

Through understanding how the T790M mutation changes binding of first generation TKIs to EGFR, second generation irreversible TKIs have been developed and are being investigated in various trials. These second generation TKIs such as neratinib and afatinib bind irreversibly to the ATP binding site of EGFR via the formation of a covalent bond. They have been shown to be able to overcome T790M driven acquired resistance. [6,34,35] Also, these TKIs can target not only EGFR/HER1 tyrosine kinase receptors, but also other members of the same class that potentiate similar downstream signaling. For example, afatinib targets EGFR/ErbB1 and ErbB2 tyrosine kinase receptors. [35] Dacomitinib is shown to be a pan-HER TKI, targeting all members of the same class, and is found to be effective against tumours harbouring T790M mutations, however, phase III trials have yet to be completed. [20,36] There are also concerns regarding the higher toxicity profile of these drugs with a narrower therapeutic window. Work on third generation EGFR TKIs are also in progress, binding covalently to the ATP site of mutant EGFR with particular specificity to the T790M mutant. [6,37]

Specific T790M inhibitors

A new class of drug that specifically targets and inhibits the T790M mutant has also been developed. [38] It is thought that targeting cancer cells which have the mutation would spare cells without the mutation and therefore remain susceptible to TKIs. Hence, mutated cancer cells with acquired resistance to TKIs can now be targeted, and the efficacy of TKIs on TKI-susceptible cancer cells is maintained.

Altering the PI3K/Akt/mTOR pathway

There is great promise in creating drugs to target this pathway as we know that levels of molecules involved in signal transduction are tightly regulated by multiple factors via many interactions. However, because this pathway is present in both cancer cells and many normal cells as well, there are concerns that drugs which alter its activity would result in pharmacological toxicities. PI3K (LY294002) and Akt inhibitors are currently being studied both as a monotherapy and as a concurrent treatment with EGFR TKIs. [39]

Another drug that has been used with great experience as an immunosuppressive agent, everolimus, is being studied for its effect on advanced NSCLC. [40] Another PI3K/mTOR inhibitor, XL765, is currently undergoing early phase trials against erlotinib alone and in combination with erlotinib. [41]

MET receptor – inhibiting amplification

Observation of the crosstalk between the HGF/MET and PI3K/AKT/ mTOR pathways has led to the hypothesis that co-administration of MET inhibitors can restore sensitivity to EGFR TKIs in resistant tumours displaying MET amplification. [42,43] In a phase II randomized trial, progression free survival (PFS) was higher when erlotinib was given with tivantinib (an agent targeting the MET receptor) as compared to erlotinib given with placebo. [44] Although this finding was not statistically significant, phase III trials are currently ongoing to explore its efficacy and related toxicities. [45]

Onartuzumab, an anti-MET receptor monoclonal antibody has shown increased PFS and overall survival when given with Erlotinib as compared to placebo. [46]

A phase I study of cabozantinib (XL184), a drug which targets both VEGF and MET receptors, has shown promise after preliminary analysis. [9]


Multiple targets with great potential are currently being investigated. Blockade of IGF-1R receptors with antibodies or molecular substrates can potentially alter downstream signaling that promotes cancer growth. [29] This can also be achieved by administration of recombinant IGF binding proteins to reduce circulating levels of IGF-1R ligands. Inhibition of the nuclear factor κB pathway is also of particular interest.

Different approaches to the treatment of EGFR positive NSCLC patients


With the observation of histological transformation as a mechanism of acquired resistance to overcome EGFR inhibition, [37] it is hypothesized that under the therapeutic stress of EGFR TKIs, the cancer cells can be encouraged to adopt this resistance mechanism and transform from a NSCLC to SCLC. Administration of EGFR TKIs can then ‘sensitize’ the cancer cells to be susceptible to platinum and etoposide based chemotherapy (standard regimen for SCLC), that would otherwise be ineffective for NSCLC.

Alternating Treatment/Different Dosing

A review by Oxnard [37] has found that although some cancer cells can acquire the T790M mutation in the presence of a EGFR TKI, this mutation becomes undetectable after a period of discontinued EGFR TKI therapy. It is explained that the T790M mutation causes suboptimal growth profile in the absence of EGFR TKIs and therefore through the notion of ‘survival of the fittest’, they are removed from the cancer population when EGFR TKIs are discontinued. This dynamic change in cancer cell profile now allows the cancer to once again be susceptible to EGFR TKI treatment. Thus, there is a biological rationale to create a dosing schedule with intervals of EGFR TKI treatment and intervals without. This would hopefully maximize cancer cell kill and improve patient outcomes.


There is a lot of potential in targeting specific parts of the complex signaling network in cancer treatment, but this runs the risk of the development of acquired resistance via compensatory pathways. Therefore, a different approach of combining multiple drugs targeting different receptors and different parts of the signaling pathway at the same time may provide a synergistic effect in limiting cancer cell growth. This can be achieved with various classes of drugs such as TKIs, downstream signal molecule inhibitors, monoclonal antibodies targeting receptors involved, immunosuppresants such as everolimus and even chemotherapy. However, trials do require adequate time, participants and investments. More effort and investigation must be performed before the best combination can be identified.

Selection of Patients

Demographically, it has been found in many articles that patients who are most likely to respond to EGFR TKIs are of Asian background (mainly Japanese), female, never-smokers and have NSCLC of the adenocarcinoma histology. [6,8,19,20,39] Presence of mutant KRAS is also found to be a strong predictor of lack of response to EGFR TKIs in NSCLC patients. [6,47,48] It is also discovered that low expression of nuclear factor κB inhibitor was predictive of poor clinical outcome for patients receiving erlotinib without a T790M mutation, indicating its potential in predicting response to EGFR TKI therapy. [18] PTEN inactivation is also a predictor of resistance to EGFR-family antagonists, implying that this subset of patients would not be amenable to long term EGFR TKI therapy. [39] These predictors not only enable us to select patients who are more likely to benefit from EGFR TKI therapy, but also help to prevent exposure of unnecessary toxicities to poor responders. With further validation of these predictors through studies, it might be even possible to develop a nomogram or scoring system to predict the success of EGFR TKIs in NSCLC patients.

Future Directions

As investigative techniques such as genotypic assessments, new assays, cell lineage tracing, chemical genomic profiling studies, next generation sequencing and proteomics develop, more information regarding tumorigenesis will be revealed. Ongoing research in other cancers may also provide insight to the pathogenesis of NSCLC. As more drugs are being released for clinical use, further research must be done to determine the short and long term side effect profiles of these drugs, whether used on their own or in combination. The fundamental principles of beneficence and non-maleficence should not be forgotten. No matter how novel or promising a drug can prove to be, its value for clinical application becomes limited when its toxicity profile causes more harm than good to patients.

It is also interesting to note that tumour signaling profiles are in a dynamic rather than static state. Mutations can be gained and lost, depending on patient’s biology, genetics and treatment received. This could mean that gathering information regarding the cancer may have to be a continuous activity rather than just prior to treatment. Patients may have to be regularly biopsied at different stages of chemotherapy or EGFR TKI treatment.

Knowing that every patient with NSCLC can have subtle differences in the biology of the cancer, future research may warrant the need to create a tumour bank where cancer cells are profiled and sequenced, both before and after treatment. This information will then be stored in a database where researchers can retrieve information from, and possibly access cell samples if required.

With the development of deep analytic systems such as the IBM supercomputer Watson, who is ‘learning’ about lung cancer at the Memorial Sloane-Kettering Cancer Centre, information from the tumour bank can be rapidly processed to generate meaningful data. Such information sharing will require an international effort, enhancing the development of targeted, higher-powered and multi-centred trials. This can drive down the high costs of drug discovery, reducing wastage of precious resources into unfruitful studies that seek to answer poorly formulated clinical questions.


The idealistic imagination of cancer cure will come in the form of personalized medicine where cancer cells are analyzed through a machine which puts together a concoction of molecules to create a single, simple tablet that will destroy the tumour entirely without side effects. As research becomes more focused into the little details of each signaling molecule in every pathway, the cumulative understanding of cancer will be heightened tremendously. The content and amount of research done is no doubt exciting and promising, but, as a clinician, our focus remains ultimately on the patient and not merely on the cancer.

Conflict of interest

None declared.


B Chua:


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Feature Articles Articles

Oral Health – An important target for public policy?


A healthy mouth is something we take for granted. We use our mouths to speak, to eat and to socialise without pain or significant embarrassment. Yet when oral disorders develop the impacts can extend well beyond the domains of speech, chewing, and swallowing to sleep, productivity, self-esteem and consequently quality of life. Despite the significant improvements made in oral health on a national scale over the last 20 years, there are still persistently high levels of oral disease and disability among Australians. This is most evident among Aboriginal and Torres Strait Islander peoples. This paper aims to review current medical literature concerning the overlap between oral health and Indigenous health outcomes and whether it may represent an important target for public health policy.


A literature review was performed through a search of The Cochrane Library, Google Scholar and Ovid Medline as well as government databases such as the Australian Institute of Health and Welfare. The terms used in the searches included: ‘Indigenous health’, ‘Aboriginal and Torres Strait Islanders’, ‘oral health’, ‘dental caries’, ‘cardiovascular disease’ and ‘education’. Limits were also set to include only studies published in the English Language and to papers published between 1995 and 2013.


Searches using combinations of the above keywords yielded more than 100 results. Article titles and abstracts were analysed for relevance to the research question and in particular any reference to Indigenous health. Specific key word limits such as ‘education’ and ‘Indigenous health’ were used to restrict the yield. Relevant articles were collated from the individual searches and bibliographies were searched for any additional points of interest. This process yielded the 17 papers reviewed for this paper.


Indigenous Health

In 2004-2008 the age-standardised death rate for Indigenous people was 1.8 times that of the non-Indigenous population; a representation of just one aspect of the ongoing issue of Indigenous disadvantage in Australia. [1] In terms of the domain of oral health there is also a wide discrepancy between both population groups. However, current literature suggests that, in the past, Indigenous Australians actually enjoyed better oral health than those who were non-Indigenous. [2] Historically, throughout the 19th and 20th centuries caries was considered to be a “disease of affluence” [3] whereas today it could potentially be a better “indicator of deprivation.” [4] Foods rich in fermentable carbohydrates are plentiful in Indigenous communities today and so is dental decay. [3] The current Indigenous health situation provides the perfect example of how a non-Western society can be detrimentally impacted upon by the introduction of Western lifestyle [5] and whilst it is not possible to discuss every aspect of this complex issue, the importance of oral health in these communities is something that requires further consideration.

The risk factors for poor oral health are the same whether someone is Indigenous or not, yet there is a disparity between the standard of oral health of both groups. According to the World Health Organisation (WHO) oral health is “being free of chronic mouth and facial pain…and disorders that affect the mouth and oral cavity.” [6] The ‘Oral health of Aboriginal and Torres Strait Islander children’ report, published by the Australian Institute of Health and Welfare, found that a higher percentage of Aboriginal and Torres Strait Islanders had experienced dental caries than other Australian children aged between four and 14 years. [7] The report further stated that children aged less than five years had almost one and a half times the rate of hospitalization for dental care when compared to their non-Indigenous counterparts. [7] A rising trend was also demonstrated in the prevalence of caries among Indigenous children, particularly in the deciduous dentition. [7] In extrapolating the causes of these inequalities it is important to consider current structural and social circumstances. These social determinants of health include aspects like socioeconomic status, transport and access, racism and housing and with the recognition of these inequalities being embedded in “a history of conflict and dispossession, loss of traditional roles…and passive welfare” a more accurate snapshot of the complicated Indigenous situation can be established. [8]

In order to best understand the issues of Indigenous health it is also important to understand how Indigenous people themselves conceptualise health. The traditional Indigenous notion of health is holistic and encompasses everything from a person’s life, body and environment to relationships, community and law; [3] a significant overlap with the social determinants model mentioned above. Whilst following a reductionist approach to medical care may be helpful in treating and managing disease, alone it is inadequate in addressing health disadvantage at a population level where a more holistic method of interpretation is required. The relationship between oral health and one’s systemic health illustrates an important area where population-focused medicine could potentially cause a reduction in rates of morbidity and mortality across multiple medical domains. Current medical research has, for example, confirmed an association exists between cardiovascular disease and periodontal disease. [9] A large retrospective cohort study performed by Morrison and colleagues (1999) reported an association between poor dental health and an increase in the incidence of fatal coronary heart disease. [10] The relationship was assessed using Poisson regression and results were adjusted for age, sex, diabetes status, serum total cholesterol, smoking and hypertensive status. [10] Rate ratios of 2.15 (95% confidence interval (CI): 1.25-3.72) and 1.90 (95% CI: 1.17-3.10) were observed in the gingivitis and edentulous status groups respectively and supported a positive association with fatal coronary heart disease. [10] A study by Joshipura and colleagues (2003), looking at 41,380 men who were free of cardiovascular disease and diabetes mellitus at baseline, suggested that periodontal disease and fewer teeth may also be associated with an increased risk of stroke. [11] During the follow up period, 349 cases of ischaemic stroke were reported, and men who had 24 or less teeth at baseline were at a higher risk of stroke than those with at least 25 teeth (hazard ratio: 1.57; 95% CI: 1.24-1.98). Furthermore, the addition of dietary factors to the model only changed the hazard ratios slightly. [11] Similar relationships have been established in linking oral infection to diabetes mellitus, low birth weight babies and disorders like otitis media and delayed growth. [3] The fact that the area of oral health has been identified as a potential risk factor for so many medical conditions highlights its importance as a target in population health.

The role of education

WHO defines health as “a state of complete physical, mental and social well being and not merely the absence of disease or infirmity.” [6] Whilst “population” is the “total number of people or things in a given place.” [12] So essentially, putting these two terms together there is an orientation towards “preventing disease, prolonging life and promoting health through organised efforts and informed choices” among whole groups rather than individuals. [12] Many of the oral health problems faced by these communities have overlapping risk factors with wider general health conditions [3] and whilst this may be a reflection of the huge amount of work that is to be done it may also be viewed as a golden opportunity, to bring positive change through the many domains of health. Improving oral health through a campaign against alcohol and tobacco will not only have positive ramifications for oral health but its effects may also be seen in the areas of general health and wellbeing. The promotion of better oral hygiene through healthier eating may also have positive developments in the rates of obesity and type two diabetes mellitus.

It is also important to mention the role of education in achieving these goals, as this tool is often the key to someone gaining the power and knowledge to change their life. Education to create awareness on how dental hygiene can improve all domains of life is important in empowering people from a population perspective. Previous studies looking at the oral health of Indigenous Australians in Port Augusta, South Australia, have revealed associations between low oral health literacy scores and self-reported oral health outcomes. [13-15] It is studies like these that have prompted the need for targeted interventions that use tailored communication and training techniques to improve oral health literacy; however, there remain few interventions actually targeting oral health literacy in Indigenous populations. [16]


Indigenous health is a complex and often controversial topic and there is much debate as to what actually needs to be done to address the huge gap. Oral health is an important field of health care that has associations with many systemic conditions and thus may provide an appropriate target for effective public health policy. Perhaps a fault in our current health care system is that the dental and medical care fields have evolved quite separately and thus many people may habitually fail to understand how a simple cavity can be linked to the rest of their being. [17] Even in the Medicare system today there are no provisions for any preventative oral health services; with the exception for low income earners being entitled to concessions for public dental treatment through the public hospital system. [3] Oral health is an integral aspect of general health and thus should be an important public health goal; especially in Indigenous communities where the high prevalence of oral disease could be prevented through population-level interventions.

Conflict of interest

None declared.


L Mclean:


[1] Thomson N, MacRae A, Brankovich J, Burns J, Catto M, Gray C et al. Overview of Australian Indigenous health status 2011. Perth: Australian Indigenous HealthInfoNet; 2012.

[2] Harford J, Spencer J, Roberts-Thomson K. Oral health, In: The health of Indigenous Australians, N. Thomson (Ed.). South Melbourne: Oxford university press; 2003. p.313-338.

[3] Shearer M and Jamieson L. Indigenous Australians and Oral Health, Oral Health Care – Prosthodontics, Periodontology, Biology, Research and Systemic Conditions [monograph on Internet]. n/a: InTech; 2012 [cited 2012 Jun 13]. Available from:

[4] Williams S, Jamieson L, MacRae A, & Gray C. Review of Indigenous oral health [monograph on Internet]. Australian Indigenous HealthInfoNet; 2011 [cited 2012 Jun 13]. Available from:

[5] Irvine J, Kirov E, Thomson, N. The Health of Indigenous Australians. Melbourne: Oxford University Press; 2003.

[6] World Health Organisation. Oral Health: Fact sheet No. 318 [homepage on Internet]; 2007 [cited 2012 Jun 13]. Available from:

[7] Australian Institute of Health and Welfare, Dental Statistics and Research Unit: Jamieson LM, Armfield JM, Roberts-Thomson KF. Oral health of Aboriginal and Torres Strait Islander children. Canberra: Australian Institute of Health and Welfare (Dental Statistics and Research Series No. 35); 2007. AIHW cat. No. DEN 167.

[8] Banks G. Overcoming indigenous disadvantage in Australia. Address to the second OECD world forum on statistics, knowledge and policy, measuring and fostering the progress of societies. Measuring and fostering the progress of societies; 27-30 Jun 2007. Istanbul, Turkey.

[9] Demmer RT, Desvarieux M. Periodontal infections and cardiovascular disease. J Am Dent Assoc. 2008 Mar;139(3):252.

[10] Morrison HI, Ellison LF, Taylor GW. Periodontal disease and risk of fatal coronary heart and cerebrovascular diseases. J Cardiovasc Risk 1999;6(1):7-11.

[11] Joshipura KJ, Hung HC, Rimm EB, Willett WC, Ascherio A. Periodontal disease, tooth loss, and incidence of ischemic stroke. Stroke 2003;34(1):47-52.

[12] Queensland Health. Understanding Population Health [monograph on Internet]. Queensland: Queensland Health; [cited 2012 Jun 10]. Available from:

[13] Jamieson LM, Parker EJ, Richards L. Using qualitative methodology to inform an Indigneous owned oral health promotion initiative. Health Prom Int 2008; 23:52-59.

[14] Williams SD, Parker EJ, Jamieson LM. Oral health-related quality of life among rural-dwelling Indigenous Australians. Aust Dent J 2010; 55:170-176.

[15] Parker EJ, Jamieson LM. Associations between Indigenous Australian oral health literacy and self-reported oral health outcomes. BMC Oral Health 2010; 10:3.

[16] Parker EJ, Misan G, Chong A, Mills H, Roberts-Thomson K, Horowitz A et al. An oral health literacy intervention for Indigenous adults in a rural setting in Australia. BMC Public Health 2012; 12:461.

[17] Widdop, F. Crossing divides: an ADRF perspective [monograph on Internet]. Australian Dental Association. Australia: Australian Dental Association; 2005 [cited 2012 Jun 13]. Available from:


Articles Feature Articles

Improving medication adherence amongst Aboriginal and Torres Strait Islander peoples


Aboriginal and Torres Strait Islander peoples represent a minority population in Australia, comprising approximately 2.5% of the total Australian population in 2011. [1] There are a number of challenges faced by Aboriginal and Torres Strait Islander peoples, due to social, economic and health differentials as a consequence of the history of marginalisation. [3] Despite improvement in detection and management of chronic disease, Aboriginal and Torres Strait Islander peoples continue to have higher incidences of chronic diseases such as cardiovascular disease and diabetes mellitus. [2,4]

A contributing factor to this gap in health statistics is a low rate of adherence to medication amongst Aboriginal and Torres Strait Islander peoples. [5] While this problem is not unique to this population, there is global evidence that the rates of adherence to medication are lower amongst marginalised groups. [6] In order to help reduce the burden of disease amongst this group, it is important to explore some reasons for non-adherence that are unique to Aboriginal and Torres Strait Islander peoples. In particular, this article will focus on the impact of cultural insensitivity and problems with access to healthcare and medications amongst this population. It will suggest how adherence can be improved through improving cultural sensitivity and access to healthcare, in order to reduce the gap in health statistics between Aboriginal and Torres Strait Islander peoples and non-Aboriginal and Torres Strait Islander peoples.

Impact of non-adherence

The World Health Organisation (WHO) estimates that, in developed countries, 50% of patients fail to comply with advice given by medical practitioners, including both medication and lifestyle advice. [6] Non-adherence with medication is a complex problem that is multi-factorial, and can contribute both to the failure of treatment [5] and increased costs to the healthcare system. [7] Often, this lack of adherence is intentional due to side effects, perceived drug effectiveness, and cost. [8] The implications of these barriers to adherence for Aboriginal and Torres Strait Islander peoples will be discussed below, with an emphasis on cultural barriers preventing adherence. [9]

Chronic diseases require adherence to medications and lifestyle modifications, in order to slow disease progression and prevent complications. [10] Therefore, non-adherence to either form of treatment can contribute to the perpetuation of this gap in health statistics. For example, in general, Aboriginal and Torres Strait Islander peoples have higher rates of cardiovascular disease than non-Aboriginal and Torres Strait Islander peoples. [3] Given that medication and lifestyle modifications reduce risk factors of cardiovascular disease and improve mortality, failure to comply with these treatments can result in exacerbation of disease rates. [3] Similarly, diabetes mellitus is a condition that is more prevalent amongst the Aboriginal and Torres Strait Islander population, and its morbidity and mortality are also disproportionately higher amongst this population. [10] Poorly controlled diabetes mellitus, through lack of adequate pharmacological management, can have serious vascular complications. This perpetuation of health inequality would in turn have a negative impact on national health expenditure, leading to increased costs to the health system. [9]

Barriers to adherence

According to the WHO, there are five dimensions that can impair a patient’s adherence with medication. [6] These are the healthcare team or system, socioeconomic factors, the nature of the therapy, the patient and the medical condition. [6] The first four dimensions are especially relevant to Aboriginal and Torres Strait Islander peoples in both rural and urban settings, and will be discussed below.

Socioeconomic factors

First, as stated by the WHO, socioeconomic factors play an important role in the low rates of adherence amongst Aboriginal and Torres Strait Islander peoples. Aboriginal and Torres Strait Islander peoples have a lower income status than non-Aboriginal and Torres Strait Islander peoples, and also have a higher unemployment rate. [11] This may therefore affect adherence to long-term, expensive medical treatment. Geographic location has previously been a barrier to accessing medications for some Aboriginal and Torres Strait Islander communities [3] and is within the WHO’s healthcare system dimension. However, the Australian Government has, in recent years, initiated national programs and legislated to improve access to prescription medications for Aboriginal and Torres Strait Islander peoples. This will be discussed below.

Cultural insensitivity

Of the Aboriginal and Torres Strait Islander peoples who do live in urban centres, many report cultural insensitivity as being the main barrier to receiving care from services that do not specialise in Aboriginal and Torres Strait Islander health. [12] This in turn can influence medication uptake and adherence. In particular, the non-Aboriginal and Torres Strait Islander healthcare system can be seen as unwelcoming. [11] This is a barrier under WHO’s healthcare team dimension. For example, one Aboriginal and Torres Strait Islander patient was unhappy because he was told to go to an Aboriginal and Torres Strait Islander health service, when he presented to a service that does not specialise in Aboriginal and Torres Strait Islander health. [12] This attitude often fosters a poor relationship between the clinician and the individual. [11]

Miscommunication between health practitioner and patient contributes to a lack of adherence to medications. For example, the services outside the Aboriginal and Torres Strait Islander system often do not provide enough support for people who only speak traditional languages within communities. [5] Cass et al. (2002) demonstrated that communication by healthcare service providers to Aboriginal and Torres Strait Islander peoples who preferred to communicate in languages other than English was often poor. [13]

Other causes of miscommunication were the health practitioner failing to share control in the consultation with the patient, failing to overcoming language barriers by not using interpreters, and using too much biomedical language during the consultation. [13] When the patient does not feel involved in decision-making, he or she is less motivated to adhere to treatment advice. [5] Furthermore, miscommunication is often unrecognised by the health practitioner, meaning that concepts are never clarified. [13] While most Aboriginal and Torres Strait Islander peoples are fluent in English, such miscommunication can have a negative impact on adherence to treatment for many people, leading in turn to adverse health outcomes. [13]

Furthermore, services that do not specialise in Aboriginal and Torres Strait Islander health sometimes do not accommodate Aboriginal and Torres Strait Islander cultural practices, which may hinder medication adherence. In some Aboriginal and Torres Strait Islander communities, traditional healers can be the first point of call for health problems. [14] Only when the traditional healers are unable to provide a solution does an individual from such a community approach the Western health system. [14] As a consequence, Aboriginal and Torres Strait Islander peoples may be less likely to comply with prescriptions due to unfamiliarity with Western medicine. [13] Furthermore, the concept of prophylactic medication does not exist in some Aboriginal and Torres Strait Islander cultures, so some community members may be reluctant to take medications that are not for the treatment of acute conditions. [15]

The family plays an important role in many Aboriginal and Torres Strait Islander people’s health. [5] Therefore, the family itself can act as a barrier to medication adherence in a number of ways. [5] First, there can be a culture of sharing medications in some communities. [5] This can result in under-treatment of the person who was prescribed the medication. Secondly, some families can influence a person’s decision to adhere to medication, by failing to support the person to adhere to medication, or by encouraging the notion that medication adherence is not cultural.[5] Therefore, educating the community and seeking familial support is important to improve adherence rates to therapies amongst some Aboriginal and Torres Strait Islander peoples. [5]

Healthcare practitioners’ role

There are a number of issues with adherence due to healthcare practitioner behaviours. First, due to cultural differences, a lack of flexibility when prescribing medication has been identified as contributing to non-adherence amongst some groups. [12] For example, health service providers are not always using long-acting medication preparations where possible, nor appropriate combination medications, to reduce the number of tablets that the patient has to take. [15] This falls under the WHO dimension of the nature of the therapy, and is something that health service providers should be aware of when engaging in culturally sensitive medical practice.

Similarly, medical practitioners themselves can be non-adherent to clinical practice guidelines when providing treatment to some Aboriginal and Torres Strait Islander peoples. [16] The study by Fürthauer et al. (2013) showed that medical practitioners may deliberately deviate from a clinical guideline for a particular patient, if they feel that the patient may not adhere to the treatment in the long-term, due to cultural practices or socioeconomic background. [16] This comes under the WHO healthcare team dimension, and is an important cause of non-adherence that needs to be examined closely in the Australian context.

The WHO states that patients should be supported, not blamed, for a lack of adherence. [6] Therefore, practitioners should take an active role to ensure that the healthcare environment supports adherence to medication. [6] For example, practitioners should work with patients to create a therapy regime that fits the patient’s lifestyle. [6] It has been shown that a shift in attitude amongst healthcare practitioners to a more empathetic, collaborative approach with their patients achieves better adherence rates. [6] This includes the practitioner taking the socio-demographic characteristics of the patient into account. [6]

History of marginalisation

In addition, some Aboriginal and Torres Strait Islander peoples feel that health services should recognise the history surrounding racism and discrimination against Aboriginal and Torres Strait Islander peoples, in order to facilitate trust and improve service uptake. [12] This issue is within WHO’s patient-specific dimension, and may eliminate any feelings of ‘cultural shame’ for accessing Western medication due to the history of marginalisation of Aboriginal and Torres Strait Islander peoples. [3] This indicates that more research needs to be undertaken on the psychological impact of marginalisation on Aboriginal and Torres Strait Islander and its link to non-adherence.

Minimising non-adherence

There are a two main ways to improve adherence rates amongst Aboriginal and Torres Strait Islander peoples. One is by improving cultural sensitivity amongst health service providers to provide appropriate services to Aboriginal and Torres Strait Islander peoples, and welcome them to services outside the Aboriginal and Torres Strait Islander system. The other way is by subsidising medications so that Aboriginal and Torres Strait Islander peoples can have better access to treatments.

Improving cultural sensitivity

In order to minimise non-adherence, it is imperative that the health system be more culturally sensitive towards Aboriginal and Torres Strait Islander peoples. [3] Service providers outside the Aboriginal and Torres Strait Islander health system need to be trained in the cultural values and healthcare beliefs of Aboriginal and Torres Strait Islander communities, in order to provide culturally sensitive advice and treatment. [3] Service providers should also be trained in communicating concepts to non-English speaking patients. [4] This involves the use of interpreters, which has been found to be beneficial in improving communication between Aboriginal and Torres Strait Islander peoples and health practitioners. [4] If required, these individuals can also be educated about medications through the use of pictures and anatomical models. [14] Similarly, medical practitioners should be encouraged to adhere to clinical guidelines when prescribing medications and to treat this group as they would any other group of patients. [16]

Another way of creating a culturally sensitive environment in healthcare centres is to better engage Aboriginal and Torres Strait Islander peoples in this process. [5] While interpreter services clearly fulfil this objective, [3] their role can be supplemented with other culturally sensitive practices. For example, Aboriginal and Torres Strait Islander peoples may feel more welcome if they see members of their communities in brochures. [5] It has been suggested that pharmacies displaying Aboriginal and Torres Strait Islander paintings and employing more Aboriginal and Torres Strait Islander staff will make Aboriginal and Torres Strait Islander peoples more likely to seek information and participate in screening programs. [5]

Increased engagement of Aboriginal and Torres Strait Islander peoples with health workers can be achieved by employing more Aboriginal and Torres Strait Islander Health Workers (AHWs), who have often lived in the region where they work. [17] AHWs act in a variety of capacities to better liaise with Aboriginal and Torres Strait Islander peoples in healthcare settings and facilitate a more positive experience. [5] They undertake clinical work, such as providing health checks and administering vaccinations, or conduct research and implement community development projects. [17] One study found that AHWs, together with pharmacists, have the potential to improve adherence with appropriate funding and education. [5] However more research needs to be undertaken to further evaluate the role of AHWs, specifically in reducing non-adherence.

A difficulty, however, in building culturally-sensitive practices, is that there are many Aboriginal and Torres Strait Islander cultures in Australia, not simply one unified culture. Therefore, a strategy that works for one group may not necessarily work for another. [5] Aboriginal and Torres Strait Islander peoples should therefore be involved in the formulation of policy strategies with health services to increase adherence. [3]

Subsidising medications

It is also necessary to consider the fiscal situation of individuals in Aboriginal and Torres Strait Islander communities. Aboriginal and Torres Strait Islander peoples have a lower median weekly household income than non-Aboriginal and Torres Strait Islander peoples. [1] Therefore, access to subsidised medication may be a way to improve adherence to medication. There are a number of initiatives funded by the Australian Government to try to improve adherence to medications.

As part of the Australian National Medicines Policy, a Quality of Use of Medicines (QUM) strategy was introduced in Australia in 1992. [18] This strategy included evaluating and improving Aboriginal and Torres Strait Islander health in remote areas through a number of ways, including the development of guidelines for culturally appropriate pharmaceutical services and evaluating medication use. [18] On the whole, it appears that the program achieved a number of its objectives, including improving Aboriginal and Torres Strait Islander health. [19] It was intended to complement a legislative change made around the same time to the National Health Act 1953.

This legislative change was made by the Australian Government to improve Aboriginal and Torres Strait Islander peoples’ access to the Pharmaceutical Benefits Scheme (PBS). Section 100 of the National Health Act 1953 gives the Minister for Health the power to make special arrangements for the supply of pharmaceutical benefits to people who are living in isolated areas, are receiving treatment for which pharmaceutical benefits are inadequate, or for whom pharmaceutical benefits can be more conveniently supplied. [20] If the Minister exercises this power, pharmacies can supply remote Aboriginal and Torres Strait Islander primary healthcare services with PBS-listed drugs in bulk, and Aboriginal and Torres Strait Islander patients can access prescription medication free of charge. [20]

The impact of this scheme on access to medications for Aboriginal and Torres Strait Islander peoples in remote areas has been evaluated. [21] It has been found that access to subsidised medications has significantly improved due to the S100. [21] However, it has been recommended that non-PBS medications commonly used by Aboriginal and Torres Strait Islander peoples should be included under S100, in order to further improve access. [21] In addition, there are limitations for people who live just outside the geographic boundaries and are not able to access the medications. [21] Therefore, it has been recommended that the section’s scope be broadened. [21]

More recently, the Australian Government Department of Health and Ageing began funding the Quality Use of Medicines Maximised for Aboriginal and Torres Strait Islander People Program (QUMAX) in 2008. [22] The aim of this program is to improve adherence with, and access to, medication amongst non-remote Aboriginal and Torres Strait Islander populations specifically. [23] This is achieved by providing financial assistance to Aboriginal and Torres Strait Islander health services to purchase medications, as well as providing patients directly with co-payments. [23] In addition, the Closing the Gap – Copayment Measure Program was introduced in 2010 to improve access to PBS medications for all Aboriginal and Torres Strait Islander peoples who are living with a chronic disease and required treatment. [24] Eligible patients are entitled to receive a waiver on the co-payment for medications under the PBS. [24]

In 2011, the Australian Government undertook an evaluation of the QUMAX and found that there was a 14% increase in PBS utilisation by Aboriginal and Torres Strait Islander peoples, especially for anti-hypertensive, lipid-lowering and asthma medications. [23] Furthermore, there was an 18% increase in utilisation among patients who were not entitled to concessional medications. [23] Some health services combined the QUMAX initiative with Aboriginal and Torres Strait Islander health assessments and care plans, which further incentivised patients to take up subsidised medications. [23]

QUMAX has arguably shown efficacy in reducing the cost barrier to accessing and complying with medications. [23] However, it is not clear whether it has eradicated inequities in PBS expenditure between Aboriginal and Torres Strait Islander and non-Aboriginal and Torres Strait Islander populations. [23] Therefore, it should continue, taking into account the recommendations set out in the evaluation. In particular, measures to address geographical barriers by providing transport for the delivery and the collection of medications should be implemented. [23] Furthermore, the recommendation to improve cultural training amongst pharmacists should be given special attention. [23]


Non-adherence with medication is a significant problem. It leads to negative health outcomes for the individual, and can result in the public health system incurring high costs. Given that the rates of non-adherence and chronic disease are greater amongst the Aboriginal and Torres Strait Islander population, specific measures need to be taken in order to minimise non-adherence. Healthcare workers should be trained to be more culturally sensitive and to provide clear, unambiguous treatment advice. They should also take care when prescribing medications to provide treatments with the lowest number of tablets appropriate. Healthcare services should be made more welcoming to Aboriginal and Torres Strait Islander peoples by including Aboriginal and Torres Strait Islander artwork, employing more Aboriginal and Torres Strait Islander staff, and involving Aboriginal and Torres Strait Islander communities in the policy-making process. Policy-makers need to be aware that there are many distinct Aboriginal and Torres Strait Islander cultures, not just a single homogenous one. Finally, medications should continue to be subsidised to Aboriginal and Torres Strait Islander peoples, to ensure that those most vulnerable to chronic illness are able to access treatment.

Conflict of interest

None declared.


S Kumble:


[1] Australian Bureau of Statistics. 2011 Census QuickStats [Internet]. 2011 [cited 2013 August 4]. Available from:

[2] Healey, J, editor. The Health of Indigenous Australians. Balmain: SpinneyPress; 2010.

[3] Davidson P, Abbott P, Davison J, DiGiacomo M. Improving Medication Uptake in Aboriginal and Torres Strait Islander Peoples. Heart Lung Circ. 2010; 19(5-6):372-7.

[4] Roe Y, Zeitz C, Fredericks B. Study Protocol: establishing good relationships between patients and health care providers while providing cardiac care. Exploring how patient-clinician engagement contributes to health disparities between Indigenous and non-Indigenous Australians in South Australia. BMC Health Serv. Res. 2012; 12:397-407.

[5] Hamrosi K, Taylor S J, Aslani P. Issues with prescribed medications in Aboriginal communities: Aboriginal Health Workers’ perspectives. Rural Remote Health. 2006; 6(2):557-569.

[6] World Health Organisation. Adherence to Long-Term Therapies Evidence for Action. Switzerland: World Health Organisation; 2003.

[7] Roller, L. Medication adherence in tribal Aboriginal children in urban situations. Curr Ther. 2002; 43(11):64-5.

[8] Laba T-L, Brien J-A, Jan S. Understanding rational non-adherence to medications. A discrete choice experiment in a community sample in Australia. BMC Fam Pract. 2012; 13(61).

[9] Donato R and Segal L. Does Australia have the appropriate health reform agenda to close the gap in Indigenous health? Aust Health Rev. 2013; 37:232-238.

[10] Bailie R, Si D, Dowden M, O’Donoghue L, Connors C, Robinson G, Cunningham J, Weeramanthri T. Improving organisational systems for diabetes care in Australian Indigenous communities. BMC Health Serv. Res. 2007; 7:67-78.

[11] Altman J. The Economic and Social Context of Indigenous Health. In: Thomson  N, editor. The Health of Indigenous Australians. Perth: Oxford University Press; 2003.

[12] Lau P, Pyett P, Burchill M, Furler J, Tynan M, Kelaher M et al. Factors influencing access to Urban General Practices and Primary Health Care by Aboriginal Australians—A qualitative study. AltNat. 2012; 8(1):66-84.

[13] Cass A, Lowell A, Christie M, Snelling PL, Flack M, Marrnganyin B et al. Sharing the true stories: improving communication between Aboriginal patients and health care workers. Med J Aust 2002; 176(10):466-470.

[14] McGrath, P. The biggest worry..’: research findings on pain management for Aboriginal and Torres Strait Islander  peoples in Northern Territory, Australia. Rural Remote Health. 2006; 6(3):549-562.

[15] Larkin C, Murray R. Assisting Aboriginal and Torres Strait Islander  patients with medication management. Aust Prescr. 2005; 28(5):123-125.

[16] Fürthauer J, Flamm M, Sönnichsen A. Patient and physician related factors of adherence

to evidence based guidelines in diabetes mellitus type 2, cardiovascular disease and prevention: a cross sectional study. BMC Fam Pract. 2013; 14(47).

[17] Mitchell M, Hussey L. The Aboriginal and Torres Strait Islander Health Worker. Med J Aust. 2006; 184(10):529-530.

[18] Emerson L, Bell K, Manning R. Quality Medication Use in Aboriginal Communities. Paper presented at: The 5th National Rural Health Conference; 1999 March 14-17; Adelaide, South Australia.

[19] Smith, A. Quality use of medicines – are we nearly there yet? Aust Prescr. 2012; 35:174-5.

[20] National Health Act 1953 [Cth] s 100.

[21] Kelaher M, Taylor-Thomson D, Harrison N, O’Donoghue L, Dunt D, Barnes T et al. Evaluation of PBS Medicine Supply Arrangements for Remote Area Aboriginal Health Services Under S100 of the National Health Act. Co-operative Research Centre for Aboriginal Health and Program Evaluation Unit, University of Melbourne. Melbourne; 2004. Report No.: RFT:102/0203.

[22] Couzos S, Sheedy V, Thiele DD. Improving Aboriginal and Torres Strait Islander  and Torres Strait Islander people’s access to medicines – the QUMAX program. Med J Aust. 2011; 195(2):62-63.

[23] Wallace A, Lopata T, Benton M, Keevy N, Jones L, Rees A et al. Evaluation of the Quality Use of Medicines Maximised for Aboriginal and Torres Strait Islander  and Torres Strait Islander Peoples (QUMAX) Program. Australia: Urbis; 2011.

[24] Medicare. Closing the Gap—PBS Co-payment Measure [Internet]. 2010 [updated 1 July 2010, cited 2013 August 5]. Available from:

Review Articles Articles

Sugammadex – the solution to our relaxant problems?

Sugammadex is the first of a class of selective relaxant binding agents. It acts by binding with high affinity to steroidal non-depolarising neuromuscular blockade drugs terminating neuromuscular blockade (NMB) through 1:1 encapsulation. Reversal of NMB has traditionally been performed by acetylcholinesterase inhibitors however these drugs have their drawbacks and are therefore not ideal.  This review examines the indications and advantages of sugammadex as well as the potential risks and shortcomings associated with its use.  Sugammadex is a relatively new drug that has been shown to be efficacious with an improved side effect profile as compared to its alternatives however several factors associated with its use have yet to be determined. These shortcomings have relevance on a therapeutic level as well as on a health economics level.


NMB has been an important development in anaesthetic practice improving operative scenarios through patient paralysis. Muscle relaxation facilitates endotracheal intubation, ensures patient immobility and improves conditions for laparoscopic abdominal surgery. [1] Broadly speaking, the two classes of agents used are the depolarising NMB agents, of which there is only one in use, and the non-depolarising NMB agents. One of the significant problems with the non-depolarising NMB agents is their propensity to cause post operative residual blockade. This side effect of the drug has both patient safety implications and economic implications. The perfect solution to post operative residual blockade is absolute reversal of a non-depolarising NMB agent. This is routinely performed by cholinesterase inhibitors. These drugs however are less than perfect, as will be discussed and come with their own side effects. [11] A relatively new drug that has appeared on the marked is sugammadex, a selective reversal agent that is considered far superior. Given the recent arrival of sugammadex to the market, its use is yet to be perfected and its risks are yet to be fully understood. Furthermore it is a very costly drug raising questions regarding cost effectiveness. This review article will look at the extent to which sugammadex is the solution to the problems associated with muscle relaxant in anaesthesia.


The study was performed through review of existing literature on sugammadex and its use.  Searches were performed using Ovid MEDLINE and the Cochrane Database of Systematic Reviews using the following terms: sugammadex, rocuronium, pancuronium, neostigmine, vecuronium, neuromuscular block, neuromuscular blockade, post operative residual block, post operative residual curarisation, post operative residual paralysis and economic assessment. Titles and abstracts were read and assessed for relevance to the paper. Bibliographies of the identified articles were hand searched to find additional relevant studies. Searches were limited to: humans and the years 2000 to current.


The Ovid MEDLINE search identified 1832 articles. Of these, 15 articles were identified as pertinent to this review. The Cochrane Database of Systematic Reviews identified one systematic review. A remaining six articles were identified from bibliographies. Therefore, a total of 21 articles were included in the final analysis.


Neuromuscular Blockade

Neuromuscular blocking agents are used on certain patients undergoing anaesthesia in addition to an anaesthetic agent and an analgesic agent. The drugs have significant risks. They pose the hazard of post-operative residual blockade which will be discussed. They are also the most common cause of anaphylaxis during anaesthesia accounting for between 60% and 70% of cases. The most commonly offending agents are rocuronium and suxamethonium. [5]

Neuromuscular blocking agents aim to totally paralyse the surgical patient by creating a blockade at the neuromuscular junction. This is not a therapeutic intervention but is rather used to facilitate endotracheal intubation, to eliminate spontaneous ventilation and to provide abdominal muscle relaxation for laparoscopic surgery. [4]

There are two classes of neuromuscular blocking drugs; depolarising agents and non-depolarising agents. Depolarising agents work by binding to nicotinic receptors causing depolarisation. They are not metabolised by acetylcholinesterase unlike acetylcholine thus prolonged activation of the receptor is produced causing paralysis. The only clinically approved depolarising agent is suxamethonium, a very short acting non-reversible drug. [22]

The other class is the non-depolarising agents. These are competitive antagonists that bind to post-synaptic nicotinic receptors preventing access and depolarisation by acetylcholine. [22] There are numerous agents under this class, notably pancuronium, rocuronium, vecuronium and mivacurium. These drugs are categorised by their length of action; pancuronium is long acting, rocuronium and vecuronium are intermediate acting and mivacurium is short acting. They are used in different scenarios depending upon procedural requirements.


Rocuronium is a commonly given non-depolarising neuromuscular blocking agent and is the primary target agent of sugammadex. It has a quick onset of action of 1-2 minutes and if given in high doses can mimic the rapid onset of suxamethonium. This is useful when considering rapid sequence induction for Caesarean section. If given in such high doses however its duration of action is lengthened behaving in a manner similar to pancuronium increasing the risk of postoperative residual blockade. It has a good side effect profile and has a 30 to 50% quicker recovery rate than pancuronium. [2,4] The problem with non-depolarising NMBDs is the risk of postoperative residual curarisation or residual NMB and the significant but small risk of anaphylaxis.

Post-operative residual neuromuscular blockade

Post-operative residual NMB presents a very real risk to surgical patients.  It is a potentially reversible condition and should be avoided where possible.  It has the potential to impair the integrity of an airway and can contribute to patient death. [6] Classic signs include airway obstruction, inadequate ventilation and hypoxia. Evidence suggests the incidence of adverse respiratory events is from 1.3 to 6.9% with one study suggesting the figure as high as 88% during the post anaesthetic care period. [7,8]  The reason for such great variability in figures is in part due to the different definitions and methods of detection.  In addition to patient risk, there is also evidence to suggest residual NMB has economic consequences contributing to operating theatre congestion and a bottleneck in patient flow. [9]

Postoperative residual blockade can be minimised through two strategies: 1) pharmacological reversal of NMBD effects and 2) optimisation of NMBD dosing through careful monitoring and titration of the relaxant. [11]

Neuromuscular Blockade Monitoring

Neuromuscular monitoring is routinely practiced, most commonly with train of four (TOF) ratios1. Classically a TOF of <0.7 was the criteria for residual NMB.  This, however, has been discredited by Murphy et al. (2009) with evidence suggesting a TOF <0.9 is required to ensure a recovery. [7] Despite increasing stringency of neuromuscular monitoring the methods are not sufficiently objective or accurate.  Naguib et al. [10] found in their meta-analysis the difference in residual NMB between TOF monitored and non-monitored patients with intermediate acting NMB agents was not statistically significant (P=0.314); however, incidence was increased with long acting NMB agents as compared with intermediate NMB agents. [10] Further methods of NMB monitoring include tidal volume, vital capacity, sustained tetanus, head lift and hand grips however all are considered inferior to TOF. [2]

Neuromuscular Blockade Reversal Agents

The other strategy for the prevention of residual paralysis is the use of pharmacological measures. Kovac et al. (2009) postulated that

“An ideal NMB reversal agent would; (1) have rapid onset; (2) be 100% effective and predictable; (3) reverse any degree of NMB; (4) be effective in the presence of potent anaesthetics; and (5) have minimal or no side effects.” [1]


The common class of drug for NMB reversal agents are cholinesterase inhibitors, the most commonly used being neostigmine. [1,2] Cholinesterase inhibitors prevent the breakdown of acetylcholine in the neuromuscular junction, increasing neuromuscular transmission. [12] Neostigmine does not have a rapid onset, with the mean time to muscle recovery being 50.4 minutes. [16] The drug cannot reverse deep NMB with TOF<0.1. [13] The drug also has a ceiling dose and can only reverse drugs of certain potencies and of certain doses. [2] Duration of action is limited and consequently residual paralysis may still be evident or paralysis may reappear post administration. [3] The drug also has significant parasympathetic side effects due to excessive stimulation of muscarinic receptors. Side effects include bradycardia, arrhythmias, nausea, vomiting, increased GIT motility, bronchospasm and excessive secretions. To prevent these side effects, anticholinergic drugs are co-administered, notably glycopyrrolate or atropine, which have their own side effects, notably tachycardia, altered cardiac conduction, dysrhythmias and urinary retention. [1,12] In addition to the side effects, anticholinesterase drugs have further limitations including their lack of predictability and unreliability. [13]

As discussed, there are significant issues with residual NMB that are clinically underappreciated. The standard reversal agents that are routinely used are not without their drawbacks; their onset is slow, their side effect profile is significant and their efficacy is insufficient in particularly deep NMB. Furthermore, monitoring methods for residual blockade are inaccurate and technically difficult.


Due to the limitations of the current class of NMB agents, sugammadex has become of interest. It is a modified cyclodextrin that has a high affinity with steroidal NMB agents (rocuronium>vecuronium>>pancuronium). [1,12] Cyclodextrins are oligosaccharides arranged in a circular shape surrounding a central cavity that can be used to bind molecules within the cavity, eliminating the target’s pharmacological action. In the case of sugammadex, cyclodextrins are modified to have a rocuronium inclusion complex. It will bind to all non-depolarising NMB agents, although with a decreased affinity. [23]

One of the major benefits of sugammadex is that unlike the anticholinesterase inhibitors, it does not interfere with the receptor systems but rather acts on the NMB agent itself, meaning there are little to no muscarinic side effects. The drug binds to the respective NMB agent rendering it unavailable at the neuromuscular junction. [12] A high dose can be given if required without a high risk of cardiovascular effects, as with neostigmine. Furthermore it does not need to be given with a muscarinic agonist, unlike anticholinesterase agents, eliminating the potential for further adverse events.

The drug is currently approved for use in Australia and the European Union; however, it is yet to be approved by the FDA in the United States. In August 2008, a not-approvable letter was issued not due to lack of efficacy but rather due to the risk of hypersensitivity and allergic reactions that had not been adequately determined. Further studies are currently being performed by Schering-Plough. [1]

The efficacy of sugammadex is well established by several significant studies. It has been shown to be a very effective NMBD reversal agent of non-depolarising NMB. Puhringer et al. (2010) reported an improvement in NMB reversal from rocuronium and vecuronium as compared with placebo, however these results represented trends and were not statistically significant. Mean rocuronium reversal times were 96.3 min with placebo and 1.5 min with sugammadex. Mean vecuronium reversal times were 79min and 3 min respectively. [20] One study by Lee et al. (2009) found that reversal of profound high dose rocuronium induced NMB with sugammadex reversal, and was substantially quicker than the use of the short acting suxamethonium. [18] Jones et al. (2008) found in a randomised comparison that sugammadex reverses profound rocuronium induced NMB significantly faster than that of neostigmine. [16] Alvarez-Gomez et al. (2007) made a similar finding in their study comparing the two drugs. [19] Sugammadex is also thought to halt relaxant induced anaphylaxis as it encircles the relaxant drugs theoretically preventing further immune reactions. However, this has not be sufficiently studied to confirm. [5] The drug has also been used successfully to reverse rocuronium induced NMB in a ‘can’t intubate can’t ventilate’ scenario. [21]

That being said there are adverse events as have been reported in 30 studies looking at 2000 patients. The most frequently reported side effects with an incidence greater than 2%, were hypotension, bronchospasm, QTc prolongation greater than 400msec, constipation, hyperactivity and altered taste sensation. Less common side effects included cough, dry mouth, temperature changes, parasthesia, parasomia, mild erythemia, abdominal discomfort, increased creatinine phosphokinase, bradycardia and dizziness. These adverse events did not appear to have a dose-response relationship. [1] While generally well tolerated, the adverse events one ought to be aware of are procedural pain, nausea and vomiting. [3]

Sugammadex can serve a purpose in rapid sequence induction. Traditionally, suxamethonium was used due to its quick speed of onset and short duration of action. However, this drug comes with a substantial list of side effects. [4] Instead, rocuronium can be given in high doses to quicken onset and can be quickly reversed at the close of the operation with sugammadex, although this is still considered second line.

The risks of residual NMB, as discussed previously, can be eliminated with the use of sugammadex. There are still some concerns for its regular use. Many studies have been conducted on the drug, looking at factors such as side effects and suitable dose ranges; however, more studies need to be conducted with larger cohorts to fully appreciate the risks. Patients with poorer health and who are more predisposed to adverse events have yet to be studied in great detail. [3]

While the cost of sugammadex is of no therapeutic relevance it needs to be taken into account from a health economics point of view. The cost is significant with a 200mg/2mL vial costing AUD188.90 and a 500mg/5mL vial costing AUD477.80 (cost sourced from FRED Dispense®, accessed 9th August 2013). It is not covered by the PBS and must be bought privately. Two systematic reviews have been performed in the UK on the cost benefit of sugammadex, both published in the British Journal of Anaesthesia. Both studies acknowledge that there could be cost benefit both from mortality and morbidity reduction point of views and with regards to optimisation of theatre time and post-anaesthetic care. However, the studies conclude that it would not be feasible to make an accurate economic assessment due to a lack of evidence. [14,15] It should be noted that these studies are UK relevant and apply differently to Australian practice. Zhang et al. (2008) found in their preliminary study of cost benefit that there is an appreciable decrease in postoperative time spent in an operating theatre improving cost efficiency; however, this failed to take into account the drug cost itself. Furthermore the study is applicable to the US health system and again may lack relevance to the Australian health system. [17]

The impetus for this paper came from an episode that occurred in theatre. A middle aged female due to receive a cholecystectomy was in an extremely anxious state before entering the operating theatre. She was convinced to go ahead with the procedure, which was uneventful. She was paralysed with rocuronium which was reversed with sugammadex. Upon reversal, the patient had a sudden severe reflexive episode going into a tonic-clonic contracture causing her jaw to occlude the endotracheal tube, in turn causing her oxygen saturation levels to fall. She had to be re-paralysed with suxamethonium to allow for manual respiration with bag and mask.

An episode as described above is not an uncommon event and can occur during the emergence from anaesthesia; however the episodes are rarely so severe. It is very possible the sugammadex can be partly blamed for the reflexive episode, with a sudden return of muscle tone increasing afferent input through the muscle and tendon stretch receptors causing the biting. Because the standard reversal agents are not as effective as sugammadex, similar reflexive episodes that have taken place will have not had the severity seen here. The drug is still very new and anaesthetists are perhaps yet to fully understand its use. With experience such events will become increasingly rare through improved use.

It has been shown convincingly that sugammadex is a superior NMB reversal agent to the cholinesterase inhibitors in terms of efficacy, although it has a significant side effect profile. Despite the considerable research that has been performed on the benefits and risks of the drug’s use, there are still many gaps in the literature which require further research.

There was no case report or evidence of similar cases to that in the clinical scenario discussed earlier. A case report of this incident may be of value. The patient’s response may have been due to incorrect dosing or indeed a rare reaction that is yet to be clinically identified.


This paper examined the use of sugammadex and its role in anaesthetic, focussing both on the risks and benefits of use. Having studied the available literature, there is a clear therapeutic benefit in the reduction of postoperative residual NMB, a preventable event that poses significant risk to patients. It presents a superior alternative to the current first line anticholinesterase NMB reversal agents. The benefit of the drug from a health economics point of view is yet to be determined, having regard to its high cost. Furthermore, the potential adverse effects and hypersensitivity reactions have not been adequately studied. The true side effect profile may require a very long period of testing or long term routine use before there is a good understanding. Sugammadex does have a role in very specific anaesthetic scenarios, however, given its significant cost and gaps in the literature, it cannot be recommended suitable for routine use.

Conflict of interest

None declared.


H Badgery:


[1] Kovac AL. Sugammadex: the first selective binding reversal agent for neuromuscular block. Journ Clin Anes.; 2009;21(6):444 – 453.

[2] Miller RD, Pardo M 2011 Basics of Anaesthesia. Sixth edition, pp 224-226

[3] Yang LPH, Keam SJ. Sugammadex: A review of its use in Anaesthetic Practice. Drugs; 2009;69(7):919 – 942.

[4] Rang HP, Dale MM, Ritter JM, Moore PK. 2003 Pharmacology, Fifth Edition. pp 149-154.

[5] McDonnell NJ, Pavy TGP, Green LK, Platt PR. Sugammadex in the management of rocuronium-induced anaphylaxis. Brit Journ Anaes; 2011;106(2):119-201.

[6] Eikermann M, Peters J, Herbstreit F. Impaired upper airway integrity by residual neuromuscular blockade: increased airway collapsibility and blunted genioglossus muscle activity in response to negative pharyngeal pressure. Anesthesiol; 2009;110(6):1253-1260.

[7] Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg; 2009;107(1):130-7.

[8] Mathias LAST, de Bernadis RCG. Postoperative Residual Paralysis. Rev Bras Anesthesiol; 2012;62(3):439-450.

[9] Butterly A, Bittner EA, George E, Sandberg WS, Eikermann M, Schmidt U. Postoperative Residual Curarization from intermediate-acting neuromuscular blocking agent delays recovery room discharge. Brit Journ Anaes; 2010;105(3):304-309.

[10] Naguib M, Kopman AF, Ensor JE. Neuromuscular monitoring and postoperative residual curarisation: a meta-analysis. Brit Journ Anaes; 2007;98(3):302-316.

[11] Maybauer DM, Geldner G, Blobner M, Pühringber, Hofmockel R, Rex C, Wulf HF, Eberhart L, Arndt C, Eikermann M. Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium. Anaes; 2007;62(1):12-17.

[12] Abrishami A, Ho J, [12] Abrishami A, Ho J, Wong J, Yin L, Chung F. Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade. Cochrane Database Syst Rev [Internet] 2009 [cited 15 Sept 2012]. Available from

[13] Magorian T, Lynam DP, Caldwell JE, Miller RD: Can early administration of neostigmine in single or repeated doses alter the course of neuromuscular recovery from a vecuronium-induced neuromuscular blockade? Anesthesiol; 1990; 73(3):410-414.

[14] Chambers D, Paulden M, Paton F, Heirs M, Duffy S, Hunter JM, Sculpher M, Woolacott N. Sugammadex for reversal of neuromuscular block after rapid sequence intubation: a systematic review and economic assessment. Brit Journ Anaes; 2010;105(5):568-575.

[15] Paton F, Paulden M, Chambers D, Heirs M, Duffy S, Hunter JM, Sculpher M, Woolacott N. Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular bloc: a systematic review and economic evaluation. Brit Journ Anaes; 2010;105(5):558-567.

[16] Jones RK, Caldwell JE, Brull SJ, Soto RG. Reversal of profound rocuronium-induced blockade with Sugammadex. A randomized comparison with neostigmine. Anesthesiol; 2008;109(5):816-824.

[17] Zhang B, Menzin J, Tran MH, Neumann PJ, Friedman M, Sussman M, Hepner D. The potential savings in operating room time associated with the use of sugammadex to reverse selected neuromuscular blocking agents: findings from a hospital efficiency model. Val Health; 2008;11(3):244.

[18] Lee C, Jahr JS, Candiotti KA, Warriner B, Zornow MH, Naguib M. Reversal of Profound Neuromuscular Block by Sugammadex Administered Three Minutes After Rocuronium: A Comparison with Spontaneous Recovery from Succinylcholine. Anesthesiol; 2009;110(5):1020-1050.

[19] Alvarez-Gomez JA, Wattiwill M, Vanacker B, Lora-Tamayo JI, Khunl-Brady KS. Reversal of vecuronium-induced shallow neuromuscular blockade is significantly faster with Sugammadex compared with neostigmine. Euro Journ Anaes; 2007;24(suppl.39):124-125.

[20] Puhringer FK, Gordon M, Demeyer I, Sparr HJ, Ingimarsson J, Klarin B, van Duijnhoven W, Heeringa M. Sugammadex rapidly reverses moderate rocuronium- or vecuronium- induced neuromuscular block during sevoflurane anaesthesia a dose-response relationship. Brit Jour Anaes; 2010;105(5):610-619.

[21] Curtis R, Lomax S, Patel B. Use of Sugammadex in a ‘can’t intubate, can’t ventilate’ situation. Brit Journ Anaes; 2012;108(4):612-614.

[22] Appiah-Ankam J, Hunter JM. Pharmacology of neuromuscular blocking drugs Contin Educ Anaesth Crit Care Pain; 2004;4(1):2-7.

[23] Baldo BA, McDonnell NJ, Pham NH. Drug-specific cyclodextrins with emphasis on sugammadex, the neuromuscular blocker rocuronium and perioperative anaphylaxis: implications for drug allergy. Clin Exp Allergy; 2011;41(12):1663-1678.


Letters Articles

National Leadership Development Seminar: developing the health care leaders of the future

The vast field of medicine transcends the mere finding of cures for ailments, seeking approaches to prolonging life, and undertaking research in the pursuit of wellbeing, important as these duties are. However, medicine’s empathetic pledge to the ill requires us to exercise leadership, amongst other qualities, as an important tool to advance the interests of both the individual and the population at large. Practical leadership and advocacy is the cornerstone of the increasingly complex environment in which 21st century healthcare is provided. Patients, institutions and communities often perceive doctors as agents of change i.e. leaders. However, some physicians may have been marginalised by the healthcare system because they either do not receive good leadership and management training, or they occupy positions that require leadership and managerial skills, which they initially do not possess. This apparent lack of appropriate leadership and management development may preclude doctors from participating in essential roles to shape the delivery of health services. [1] The problem can be traced back to medical school, where relatively little, or perhaps non-existent emphasis is given to nourish medical students’ attitudes towards leadership. Current medical curricula offer students little leadership education of the kind considered necessary to develop competences essential in becoming actively involved in the planning, implementation and provision of patient care. [2]

The Australian Medical Students’ Association (AMSA), being the peak advocating body for key affairs that concern medical students across the country, has identified this issue. It has responded by establishing the National Leadership Development Seminar (NLDS), an initiative aimed to assist motivated students interested in leading the medical profession. Each year, since its inception in 2005, NLDS attracts hundreds of applications from bright students who are keen to enhance their leadership skills. The seminar allows for approximately 90 applicants to participate annually. The NLDS program is carefully constructed to equip attendees with knowledge, skills and attitudes regarding leadership, advocacy and management, with a focus on current national health issues. The three-day seminar, which is held in Canberra, integrates guest speaker presentations, small group activities and interactive workshops to teach students how to link necessary leadership competencies with actual service opportunities.

The NLDS focus on leadership is closely aligned with Health LEADS Australia, a health professional leadership framework draft that has recently been published by Health Workforce Australia. The framework describes some of the most important leadership attributes that health workers who are involved in building a flourishing and sustainable health system should embrace and promote. This leadership framework is divided into five arms, including emotional intelligence and self-performance reflection, acknowledging the abilities of others whilst helping them to develop, and concentrating on achieving goals and pursuing innovative change. [3]

Although long term evaluation data is required to assess the effectiveness of NLDS (especially in meeting the key objective competences as outlined by Health LEADS Australia and Domain 4 of the Australian Medical Council’s Graduate Outcome Statements [4]), this program offers an innovative model of a leadership-based course. This can have a positive impact on leadership skills development among medical school students and can be incorporated into the medical school curriculum. We understand that NLDS has some limitations in terms of its primordial structure compared to other more established leadership programs in the realm of business and economics. These limitations include the program’s exclusivity to only a minor number of students per year, non-exhaustive coverage of all aspects of what it takes to become a successful leader in the clinical arena, and lack of networking past the event’s conclusion. Despite these drawbacks, NLDS is a unique national attempt to illustrate the importance of leadership in medical education. We invite medical schools to look at NLDS as a template whilst designing an innovative, socially accountable curriculum to engage students in the practices of advocacy, management and leadership.

Conflict of interest

None declared.


L Ngu:


[1] Abbas MR, Quince TA, Wood DF, Benson JA. Attitudes of medical students to medical leadership and management: a systematic review to inform curriculum development. BMC Med Educ. 2011;11:93.

[2] O’Connell MT, Pascoe JM. Undergraduate medical education for the 21st century: leadership and teamwork. Fam Med. 2004 Jan; 36 Suppl:S51-S56.

[3] Health LEADS Australia: Consultation for an Australian Health Leadership Framework: Health Workforce Australia; 2012. [cited July 2013]. Available from:

[4] Accreditation Standards for Primary Medical Education Providers and their Program of Study and Graduate Outcome Statements: Australian Medical Council; 2012. [cited July 2013]. Available from:

Case Reports Articles

Acute viral bronchiolitis in the setting of extensive family history of asthma

This case report describes a previously healthy eleven-month old ex-preterm female with a severe presentation of acute viral bronchiolitis with an extensive family history of asthma. The link between viral bronchiolitis and asthma has always been controversial despite extensive research. Several studies have linked respiratory syncytial virus (RSV) bronchiolitis to the development of persistent wheezing or asthma later in childhood, even suggesting that a dose-response relationship may exist between the two entities. Some studies have also demonstrated that severe lower respiratory infections in the first year of life are important contributors to asthma, particular in those sensitized during infancy. On the other hand, it has also been studied as to whether an individual at risk of asthma has any impact on the severity of bronchiolitis. Despite numerous studies, results have largely been inconclusive, and the question of whether it is RSV that directly results in asthma, or if the susceptibility to RSV is conferred due to predisposing pulmonary pathology, still remains unknown.


Sally was an eleven-month old ex-preterm (35 weeks) female who presented to the Emergency Department (ED) with symptoms of fever, coryzal symptoms and a wheeze, subsequently diagnosed as viral bronchiolitis.


Sally had become acutely febrile two nights prior to presentation, developing coryzal symptoms the following morning. Sally was initially treated for an upper respiratory tract infection (URTI) and acute otitis media with amoxicillin by her general practitioner, but began to worsen over the subsequent 24 hours, with laborious and wheezy breathing, coupled with a persistent fever of 38.4oC. Despite two doses of salbutamol, her breathing continued to deteriorate, leading to her presentation at the ED. There were no apnoeic or cyanotic episodes, rigors or any associated inspiratory stridor. During this period, Sally was anorexic, with subsequently fewer nappy changes, and was reported by her parents to be far less active than usual. She was previously well, with no known sick contacts, and her vaccinations were up-to-date.

Sally had a similar episode of bronchiolitis in at eight months of age but was treated then as an outpatient. There was an extensive family history of asthma (Figure 1), and both the patient’s siblings had bronchiolitis as infants. At eleven months, Sally was meeting all the developmental parameters for her age. There were no known drug allergies and other than salbutamol PRN, the patient was not on any other medication. There was no remarkable social history.


Sally appeared lethargic and was in respiratory distress, with tachypnoea, an audible wheeze and classical signs of increased breathing effort (nasal flaring, tracheal tug and subcostal recession). She had a respiratory rate of 78 and was saturating at 100% on 8L supplementary oxygen, which decreased to 90% on room air, and was febrile at 38.5oC. She was tachycardic at a heart rate of 170. There were no clinical signs of dehydration. On auscultation, air entry was reduced bilaterally, with an expiratory wheeze and diffuse crackles present. There was no evidence of stridor, increased vocal resonance, or dullness to percussion. An ear, nose and throat examination revealed an erythematous pharynx but was otherwise unremarkable. All other examination findings were unremarkable.

Workup and Progress

The presenting symptoms suggested a diagnosis of acute viral bronchiolitis. However, with the extensive family history of asthma, Sally’s presentation could be her first virus- triggered asthma attack. While the clinical presentation suggested otherwise, there were concerns over the possibility of pneumonia, which had to be ruled out in the workup. In consideration of the severity of her initial presentation and the likely further deterioration until its peak at day 2-3, basic investigations were ordered. These included a full blood count, urea, electrolytes and creatinine parameters, a chest X-ray and a nasopharyngeal aspirate. There were no abnormal findings.

Sally was commenced on immediate supportive therapy. An IV line was inserted and she was commenced on 75% maintenance fluids as per guidelines to avoid Syndrome of Inappropriate Antidiuretic Syndrome. [1] She was also commenced initially on 2L oxygen as per guidelines for respiratory distress, [2] but failed to saturate appropriately until given 8L of humidified oxygen via nasal prongs, where she maintained 100% O2 saturation. While the efficacy of short-acting beta agonists (SABAs) in the acute management of bronchiolitis has been inconclusive despite extensive research, current guidelines recommended a trial of bronchodilators in infants >6 months. [3] Sally was administered six puffs of Salbutamol MDI (100mcg/ puff) via spacer [1] but with no results, hence the regime was discontinued.

The Royal Children’s Hospital (RCH) provides further guidance regarding management based on clinical signs and symptoms. Admission to the intensive care unit (ICU) was indicated for Sally to allow continuous cardiorespiratory monitoring and supportive management. Observations were performed hourly and with only supportive management, her oxygen requirements were weaned down to 2L over 24 hours.


Bronchiolitis during infancy and asthma in childhood – is there a causal link? Should infants at high risk of asthma receive Palivizumab immunization?

Several studies have linked respiratory syncytial virus (RSV) bronchiolitis to the development of persistent wheezing or asthma later in childhood. In a long-term prospective cohort study, there was a relative risk of 2.8 of developing wheezing at 5.5 years in children who had had bronchiolitis. [4] Sigurs et al. (2005) also reported a ten-fold excess of asthma in a similar study. [5]

It has also been suggested that a dose-response relationship exists between bronchiolitis and asthma. In a study involving 90,341 children, Carroll et al. (2009) demonstrated that the odds ratios (OR) for asthma as a child were 1.86 (95% CI, 1.7-2.0), 2.41 (95% CI, 2.2-2.6) and 2.8 (95% CI, 2.6-3.0) in the outpatient, ED, and hospitalization groups, respectively, compared to children without bronchiolitis. [6] Henderson et al. (2005) also noted an OR of 2.5 (95% CI 1.4-4.3) of developing asthma with hospitalization for RSV bronchiolitis, [7] as did two prospective studies, which showed a 30-40% likelihood of subsequent asthma. [8]

RSV bronchiolitis as a direct cause of asthma

In an extensive seven-year REBEL prospective cohort study, Bacharier et al. (2012) reported that increased Chemokine (C-C motif) Ligand 5 (CCL5) expression in nasal epithelial cells during RSV infection carried an OR of 3.8 (95% CI, 1.2-2.4) for developing asthma. [9] This is in concordance with studies demonstrating increased CCL5 levels in subjects with asthma, [10] as well as in vitro studies demonstrating increased expression and transcription by RSV. [11] Unfortunately, the study failed to measure CCL5 levels prior to infection and thus the causal relationship has not been established. Hence, whether it was RSV that directly resulted in asthma, or if the susceptibility to RSV was conferred due to predisposing pulmonary pathology, [12] still remains unknown.

A five-year cohort study on children at high risk of atopy by Kusel et al. (2007) demonstrated that severe lower respiratory infections in the first year of life are important contributors to asthma, particular in those sensitized during infancy. [13] These findings suggest that protecting high-risk individuals from infection during infancy may be considered for long-term asthma prevention.

Effect of family history of asthma or atopy on severity of bronchiolitis

It has also been studied whether an individual at risk of asthma has any impact on the severity of bronchiolitis. This was particularly relevant in the Sally’s case, with her significant family history of asthma. Results in this field have been conflicting, with most studies not eliciting any significant association. However, Gurwitz et al. (1981) demonstrated that hospitalized cases were associated with a higher incidence of first-degree relatives with bronchial hyper-responsiveness. [14] A study by Trefny et al. (2000) also demonstrated similar results. [15]

Should high-risk atopic individuals receive Palivizumab immunization during RSV season for prevention of asthma?

Passive immunization with Palivizumab is currently recommended only for high-risk infants to prevent serious complications arising from RSV infections. [16] However, a recent double-blinded RCT in the Netherlands has begun examining its preventive effect on recurrent wheeze in healthy preterm children 33-35 weeks gestational age (MAKI trial), based on a non-randomized trial suggesting a prevention of wheeze in 50% of preterm children. [17] Such a study would complement this case study’s patient profile, and would be especially relevant in the context of her rich family history of asthma which puts her at high risk, and the abovementioned association but inconclusive causation between bronchiolitis and asthma.

From an economic standpoint, studies assessed the cost-effectiveness of Palivizumab, albeit in the context of high-risk premature infants (32-35 weeks). Unfortunately, the predisposition of these infants to a higher disease burden and costlier hospitalizations constitutes a higher cost per QALY [18]      compared to this case study’s patient, but even then there is still considerable controversy over its cost-effectiveness, especially across various healthcare systems.


In summary, this was a case of severe viral bronchiolitis warranting ICU admission for supportive management, on a background of an extensive family history of asthma. While studies have shown a clear association of bronchiolitis with asthma, causation has not been conclusively established, with family history of atopy possibly interacting in the development of asthma. Current research is lacking in the area of Palivizumab prophylaxis in the interest of asthma prevention in healthy children, but the evidence would suggest that it is likely to be cost-ineffective.

Conflict of interest

None declared.


G Yong:


[1] Royal Children’s Hospital. Bronchiolitis- Ongoing Management. (accessed 11 March 2013)

[2] Royal Children’s Hospital. Oxygen Delivery. (accessed 11 March 2013)

[3] [Guideline] Diagnosis and management of bronchiolitis. Pediatrics. 2006 Oct;118(4):1774-93.

[4] Murray M, Webb MS, O’Callaghan C, Swarbrick AS, Milner AD. Respiratory status and allergy after bronchiolitis. Arch Dis Child. 1992 April;67(4): 482-7.

[5] Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med. 2000;161:1501–7.

[6] Carrol KN, Wu P, Gebretsadik T, Griffin MR, Dupont WD, Mitchel EF, Hartert TV. The severity- dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. Journal of Allergy & Clinical Immunology 2009;123:1055-61.

[7] Henderson J, Hilliard TN, Sherriff A, Stalker D, Al Shammari N, Thomas HM. Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: a longitudinal birth cohort study. Pediatric Allergy Immunology. 2005;16:386–92.

[8] Sign AM, Moore PE, Gern JE, Lemanske RF, Hartert TV. Bronchiolitis to asthma A review and call for studies of gene-virus interactions in asthma causation. Am J. Respir. Crit Care Med. January15 2007;175(2):108-19.

[9] Bacharier LB, Cohen R, Schweiger T, Yin-Declue H, Christie C, Zheng J et al. Determinants of asthma after severe respiratory syncytial virus bronchiolitis. Journal of Allergy & Clinical Immunology 2012;130:91-100.

[10] Humbert M, Ying S, Corrigan C, Menz G, Barkans J, Pfister R et al. Bronchial mucosal expression of the genes encoding chemokines RANTES and MCP-3 in symptomatic atopic and nonatopic asthmatics: relationship to the eosinophilactive cytokines interleukin (IL)-5, granulocyte macrophage-colony-stimulating factor, and IL-3. Am J Respir Cell Mol Biol 1997;16:1-8.

[11] Koga S, Novick AC, Toma H, Fairchild RL. CD81T cells produce RANTES during acute rejection of murine allogeneic skin grafts. Transplantation 1999;67:854-64.

[12] Adamko DJ, Friesen M. Why does respiratory syncytial virus appear to cause asthma? Journal of Allergy & Clinical Immunology 2012 Jul;130(1):101-2.

[13] Kusel MM,  de Klerk NH, Kebadze T Vohma V, Holt PG, Johnston SL et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. Journal of Allergy & Clinical Immunology 2007;119:1105-10.

[14] Gurwitz D, Mindorff C, Levison H. Increased incidence of bronchial reactivity in children with a history of bronchiolitis. J Pediatr 1981;98:551–5.

[15] Trefny P, Stricker T, Baerlocher C, Sennhauser FH. Family history of atopy and clinical course of RSV infection in ambulatory and hospitalized infants. Pediatric Pulmonology 2000;30:302–6.

[16] Wang D, Byliss S, Meads C. Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: a systematic review and additional economic modelling of subgroup analyses. Health Technol Assess 2011 Jan;15(5):1-124.

[17] Broughton S, Bhat R, Roberts A, Zuckerman M, Rafferty G, Greenough A. Diminished lung function, RSV infection, and respiratory morbidity in prematurely born infants. Arch Dis Child Jan 2006;91(1):26-30.

[18] Smart KA, Paes BA, Lanctot KL. Changing costs and the impact of RSV prophylaxis. Journal of Medical Economics. 2010;13(4):705-8.



Case Reports Articles

A case of solid pericardial metastases causing constrictive pericarditis in a patient with non small cell lung cancer

Introduction: Cardiac metastases are rarely diagnosed in patients with cancer despite being a common finding at autopsy. We report on a case of pericardial metastases in a patient with non small cell lung cancer (NSCLC) in the setting of coexisting direct tumour invasion into the superior vena cava (SVC) and right atrium. Case: We present a case of a 61-year old gentleman with metastatic adenocarcinoma of the lung. He presented with 2 – 3 days of progressive dyspnoea associated with pre-syncope. His physical examination was significant for bilateral elevated jugular venous pressure (JVP), bilateral arm oedema and hypotension. These clinical signs were explained by solid pericardial metastases causing constrictive pericarditis in the absence of significant pericardial effusion, and direct invasion of tumour into the SVC and right atrium producing SVC obstruction. His admission was complicated by an episode of supraventricular tachycardia (SVT), presumably caused by compromise of the electrical conduction system within the right atrium. Discussion: Cardiac metastasis is a common occurrence in advanced neoplastic disease, but is often clinically silent. The mechanism of cardiac metastases is believed to be primarily through lymphatic channels and metastasis is most commonly located in the pericardium. Symptoms of cardiac metastasis can be understood with respect to their anatomical position and are best diagnosed using transoesophageal echocardiogram (TOE). The most concerning complication of metastasis to the heart is pericardial effusion leading to life-threatening cardiac tamponade. This is an oncological emergency and is treated with pericardiocentesis and follow up preventative measures. Ultimately, cardiac metastasis signals advanced disease and poor prognosis.


Cardiac metastases occur in 20-30% of patients with non small cell lung cancer (NSCLC) [1] but are clinically silent in the majority of cases. [2] We report on a case of constrictive pericarditis caused by solid pericardial metastases concurrent with direct invasion of tumour into the superior vena cava (SVC) and right atrium. The clinical picture was complicated by SVC obstruction and right atrial compromise causing supraventricular tachycardia (SVT).

The case

The patient was a 61-year old store worker with a previous 60 pack-year smoking history.  He was admitted with progressive dyspnoea over 2-3 days, associated with pre-syncope, on a background of metastatic NSCLC (T4N0M1b).

Past Medical History

The patient initially presented with a six month history of pain when abducting his right arm, which was associated with dyspnoea and a productive cough. A chest computed tomography (CT) identified a large right hilar lesion causing right middle lobe bronchus occlusion and collapse of the right lung. The tumour had invaded the mediastinum, and was attenuating the SVC and compromising the right atrium. Metastases to the liver, the right sternoclavicular joint and the 4th, 9th and 10th ribs were also identified.

Pathology from the bronchoscopy biopsy demonstrated that the tumour was p63 negative and Thyroid Transcription Factor 1 (TTF-1) positive via immunohistochemical staining, consistent with adenocarcinoma of the lung. Epidermal Growth Factor Receptor (EGFR) screening was negative, hence the tumour was not sensitive to treatment to EGFR tyrosine kinase inhibitors. His management plan, following multidisciplinary team discussion, was radiotherapy to his chest and clavicle for pain management, and palliative chemotherapy (carboplatin/paclitaxel).

Three months post initial diagnosis, restaging CT of the chest, abdomen, pelvis and lumbar spine was organised after completion of radiotherapy and two cycles of chemotherapy. CT scans of the chest, abdomen and pelvis showed disease progression with new right adrenal metastases and new pericardial metastases (Figures 1 and 2). CT of his lumbar spine revealed disease in L1-2 and S1. In light of his latest CT results, radiotherapy to the lumbar spine and pericardium was planned.

Medications and Allergies

At time of admission the patient’s medications included oxycodone/naloxone, omeprazole and dexamethasone. He was allergic to penicillin.

Inpatient Admission

The patient was admitted after worsening dyspnoea was noticed during radiotherapy to his lumbar spine. Initial physical examination revealed mild bilateral pitting oedema at the ankle and no other signs. His initial investigations included full blood examination (FBE), urea, electrolytes and creatinine (UEC), liver function tests (LFTs), and calcium, magnesium and phosphate (CMP). All were normal except for a decrease in haemoglobin (Hb: 83). A provisional diagnosis of anaemia secondary to chemotherapy or neoplastic disease was made based on his haemoglobin, and he was given two units of packed red blood cells.

The following morning, the patient’s dyspnoea had not improved with transfusion.  On examination, his jugular venous pressure (JVP) was elevated bilaterally at four centimetres, his arms were swollen bilaterally and his blood pressure (BP) was 95/55. He was not tachycardic. An urgent electrocardiogram (ECG) and transthoracic echocardiogram (TOE) was performed to exclude cardiac tamponade. ECG was normal and a pericardial effusion, though noted on TOE, was trivial and deemed insufficient to cause cardiac tamponade. However, the echocardiogram demonstrated pericardial metastases overlying the left and right ventricular apex as well as the lateral left ventricular wall and inferior right ventricular wall. Significant echocardiography findings consistent with constrictive pericarditis included abnormal septal motion with marked septal bounce, annulus reversus on tissue Doppler, and left diastolic dysfunction with shortened deceleration time.

On day three of his admission, the patient had an episode of supraventricular tachycardia. His tachycardia was asymptomatic and he was treated conservatively with fluid hydration. Fluid resuscitation was unsuccessful and he remained tachycardic and hypotensive. Amiodarone 200mg was delivered and his heart rate and BP normalised gradually over eight hours. Electrolyte replacement was also initiated after UEC and CMP results revealed mildly decreased potassium and magnesium.


The patient remained as an inpatient for a further two weeks, amiodarone was gradually reduced from 200mg three times daily to 200mg daily and he had no further episodes of SVT. He completed radiotherapy to his lumbar spine and pericardium. Chemotherapy was ceased due to disease progression and functional decline.

Before discharge, the patient enquired about his prognosis which was carefully explained to him and communicated to his family. He was discharged to a palliative care unit, where he died six days later.


Cardiac metastases are rare clinical ante-mortem diagnoses, as they are silent in more than 90% of patients. [2] Most cases of cardiac metastases are diagnosed post-mortem and, as a result, most epidemiological data regarding cardiac metastases are from autopsy results. The reported incidence according to the literature up to 15% [3] in oncology patients.  An increased incidence has been reported due to modern diagnostic tools and improved survival of cancer patients, secondary to improved treatment and change in the natural cancer history. [2]

In theory, any primary malignancy has the potential to spread to the heart. The rates of metastasis in different tumour types were reported by Bussani et al. in 2007 [4] in a review of post-mortem studies performed at the University of Trieste, Italy, where over 80% of in-hospital deaths are examined by autopsy. They reviewed data from 1994 to 2003 and their reported rates of cardiac metastasis in different tumour types is summarised in the table below (Table 1). Currently, the only tumours which have not been demonstrated to metastasise to the heart are central nervous system tumours. [5]

Tumours can spread to the heart via one of four routes: 1) direct invasion, 2) haematogenous spread, 3) lymphatic spread and 4) intracavitary diffusion. [4] Tumours which originate near the heart, such as bronchial and oesophageal tumours, can directly invade the heart. Lymphatic channels facilitate pericardial metastases, whereas haematogenous routes seed myocardial metastases. [5] Endocardial metastases arise from a combination of haematogenous and intracavitary diffusion through other layers of the heart. [4]

The most common site of cardiac metastases is the pericardium, followed by the myocardium and endocardium. [4-7] With a preference for lymphatic spread, lung and breast carcinomas commonly spread to the pericardium, whereas lymphomas, leukaemias, sarcomas and malignant melanomas spread haematogenously and seed in the myocardium. [5] Only in isolated cases has there been tumour spread to the valves. [4,7]

Clinical evidence of cardiac metastases is variable ante-mortem. However, common presenting symptoms of cardiac involvement include dyspnoea, cough, palpitations, syncope and chest pain. [2] Presentations of cardiac metastases may be obscured by symptoms of advancing primary malignancy, but they can also present as life-threatening emergencies, such as cardiac tamponade, myocardial rupture, ventricular arrhythmia and, rarely, acute myocardial infarction. [2] In some cases, the rise of symptoms from cardiac involvement may be the only indication of an underlying malignancy. [8,9]

In our case, cardiac metastases presented with dyspnoea and elevated JVP. Relevant differentials for dyspnoea associated with elevated JVP included intracardiac SVC obstruction, cardiac tamponade, constrictive pericarditis, radiation pericarditis and restrictive cardiomyopathy. CT chest demonstrated SVC obstruction, and echocardiography findings were suggestive of constrictive pericarditis caused by solid pericardial metastases. As such, the patient’s dyspnoea and elevated JVP were likely to have been caused by a combination of tumour compression of the SVC reducing venous return to the right atrium and impaired diastolic filling due to an inelastic pericardium in constrictive pericarditis.

Presentations of cardiac metastases can be explained by the anatomical position of the metastases. Pericardial lesions cause pericarditis, which lead to serosanguineous or haemorrhagic pericardial effusions and, in most cases, cardiac tamponade. [5] Replacement of the myocardium and endocardium with tumour can cause systolic or diastolic heart failure, particularly if the ventricles are involved. [4] Myocardial infarctions occur when a neoplasm-induced embolus occludes the coronary circulation, or when coronary arteries are directly compressed or invaded by tumour or pericardial effusion. [4] Arrhythmias are common in the setting of any neoplastic involvement of the heart. [10]

The investigation of choice in detecting cardiac metastases is transoesophageal echocardiography. [5] Pericardial involvement is strongly indicated by a thickened pericardium, or in some cases, as a cauliflower-like projection into the pericardial fluid space. [11] Pericardial effusions can be detected with high sensitivity, and pericardiocentesis can be immediately performed under ultrasound guidance, quickly verifying the diagnosis of metastatic disease. Other imaging modalities such as MRI and CT can determine the size and extension of the tumour more precisely, and provide information on the characteristics of the lesion. [5,12] As such, myocardial metastases are better demarcated by CT and MRI over ultrasonography.

ECG findings in cardiac metastases are non-specific, although more than two thirds of patients with cardiac metastases show some degree of abnormality. [2] Similarly, chest radiography has limited use, but may reveal an increased cardiac silhouette from pericardial effusion or pericardial tumour. Chest radiography may demonstrate a primary lung tumour or pleural effusion resulting from heart failure. [5] There have been rare cases of osteogenic sarcoma metastases to the heart which contained bone and were visualised on the chest radiography.  [13]

Biopsy of cardiac metastases is rarely indicated, as less invasive imaging techniques are usually adequate to suggest tumour type and determine if surgery is feasible. However, biopsies of the heart can be done using fluoroscopy- or ultrasound-guided techniques, or through open surgery. [5] Coronary angiogram studies have value in surgical planning. However, the above techniques are rarely utilised in secondary cardiac tumours, and are more significant in the evaluation of likely primary tumours. [5,14]

Surgical treatment of cardiac tumours is uncommon and reserved for those with good long-term prognosis. Radiotherapy is commonly used to relieve local symptoms, provide local control and obtain haemodynamic stability. [2] Chemotherapy is also employed if the tumour is chemo-sensitive, as in the case of lymphomas, leukaemias and germ cell tumours. The life expectancy of pericardial metastases without treatment is reported to be 1.75 weeks. [15] With treatment, namely radiotherapy and periocentesis when necessary, life expectancy was extended to 22.5 weeks. [15]

Immediate treatment is required in patients presenting with pericardial effusions leading to life-threatening cardiac tamponade. Drainage of the pericardial fluid by pericardiocentesis is required, but effusions return in up to 60% of cases. [16] Thus, treatment of the initial effusion is combined with prevention of recurrence, which can be achieved with prolonged catheter drainage, obliteration of the pericardial space or creation of a permanent pericardial window which drains into the pleural or peritoneal cavity. The utilisation of sclerosing agents and instillation of chemotherapeutic agents in the pericardium have also been shown to prevent effusions. [2]


This case demonstrates salient features of cardiac involvement in metastatic lung cancer, including primary invasion into the SVC and right atrium as well as metastatic involvement of the pericardium. While most cardiac metastases are silent, or obscured by advanced disease, this case has highlighted clinical complications of cardiac involvement, including SVC obstruction, SVT and constrictive pericarditis.  Suspicion of cardiac metastases should always be high in oncology, as it allows prompt treatment and optimal comfort of the patient.

Consent declaration

Informed consent was obtained from the patient for publication of this case report and accompanying figures.


The authors would like to thank Dr. Vishal Boolell and Dr. Peter Briggs for their advice and supervision.

Conflict of interest

None declared.


J Ng:


[1] Tamura A, Matsubara O, Yoshimura N, Kasuga T, Akagawa S, Aoki N. Cardiac metastasis of lung cancer. A study of metastatic pathways and clinical manifestations. Cancer 1992;70(2):437-42.

[2] Al-Mamgani A, Baartman L, Baaijens M, de Pree I, Incrocci L, Levendag PC. Cardiac metastases. Int J Clin Oncol 2008;13(4):369-72.

[3] Mukai T, Shinka T, Tominaga K, Shimosata Y. The incidence of secondary tumours of the heart and pericardium: a 10-year study. Jpn J Clin Oncol 1988;18(3):195–201.

[4] Bussani R, De-Giorgio F, Abbate A, Silvestri F. Cardiac metastases. J Clin Pathol 2007;60(1):27-34.

[5] Reynen K, Kockeritz U, Strasser RH. Metastases to the heart. Ann Oncol 2004;15(3): 375-81.

[6] Klatt EC, Heitz DR. Cardiac Metastases. Cancer 1990;65(6):1456-9.

[7] Malaret GE, Aliaga P. Metastatic disease to the heart. Cancer 1968;22(2):457-66.

[8] Imazio M, Demichelis B, Parrini I, Favro E, Beqaraj F, Cecchi E, Pomari F, Demarie D, Ghisio A, Belli R, Bobbio M, Trinchero R. Relation of acute pericardial disease to malignancy. Am J Cardiol. 2005;95(11):1393-4.

[9] Sosinska-Mielcarek K, Sosvinska-Mielcarek K, Senkus-Konefka E, Jassem J, Kulczycka J, Jendrzejewski J, Jaskiewicz K. Cardiac involvement at presentation of non-small-cell lung cancer.J Clin Oncol. 2008;26(6):1010-1.

[10] Nakamura A, Suchi T, Mizuno Y. The effect of malignant neoplasms on the heart: a study on the electrographic abnormalities and the anatomical findings in cases with and without cardiac involvement. Jpn Circ J. 1975;39(5):531-42.

[11] Chandraratna PA, Aronow WS. Detection of pericardial metastases by cross-sectional echocardiography. Circulation 1981;63(1):197–199.

[12] Chiles C, Woodard PK, Gutierrez FR, Link KM. Metastatic involvement of the heart and pericardium: CT and MR imaging. Radiographics  2001;21(2):439-49.

[13] Seibert KA, Rettenmier CW, Waller BF, Battle WE, Levine AS, Roberts WC. Osteogenic sarcoma metastatic to the heart. Am J Med 1982; 73(1):136–141.

[14] Vander Salm TJ. Unusual primary tumours of the heart. Semin Thorac Cardiovasc Surg 2000;12(2):89-100.

[15] Quaraishi MA, Constanzi JJ, Honkanson J. The natural history of lung cancer with pericardial metastases. Cancer 1983;51(4):740-2.

[16] Tsang TS, Seward JB, Barnes ME, Bailey KR, Sinak LJ, Urban LH, Hayes SN. Outcomes of primary and secondary treatment of pericardial effusion in patients with malignancy. Mayo Clin Proc 2000;75(3):248-53.

Original Research Articles Articles

Social phobia in children – risk and resilience factors

Introduction: Anxiety disorders account for one third of psychiatric complaints that young people present to their general practitioners with. Social phobia (SP) is one of the most prevalent of these disorders, in children and adolescents. Methods: Sixty nine patients with carefully defined SP and a control group of 129 typically developing (TD) children were recruited through the Academic Child Psychiatry Unit, Royal Children’s Hospital. All completed the McMasters Family Assessment Device, Hopkins Symptom Checklist, and the Spanier Dyadic Adjustment Scale. Results: There were no clinically meaningful differences in family functioning between the SP group and TD group. Parents of children with social phobia reported higher rates of anxious (η2 = 0.10), obsessive compulsive (η2 = 0.12) and depressive (η2 = 0.13) symptoms, compared to parents of the control group. Furthermore, the relationships of parents with children who have SP appeared to be unhappier (η2 = 0.15) and they reported working together less (η2 = 0.14) than their counterparts. Discussion: Although family functioning per se is not associated with an increased risk of SP in children, the presence of dysfunction tends to lead to protracted SP. Moreover, the stress of having a family member with a mental illness can impact on the parental relationship, causing problems. This may or may not be related to parents of young people with SP displaying symptoms of anxiety, obsessive-compulsiveness and depression. This supports the need to consider both the parents and children when constructing a management plan, which can be initiated and executed by general practitioners.


Mental health problems are prevalent amongst young people, with almost one in four experiencing some impairing difficulties in their adolescence. [1] While the first port of call for Australian children tends to be their general practitioners (GP), it is estimated that out of the 25% who seek help, there are at least twice as many who actually have mental health issues, since most young people present with somatic complaints. [1,2] Anxiety disorders are one of the commonest psychiatric problems and over a third of young people who present to their GPs have symptoms of anxiety and depression. [1-3] Social phobia (SP) is a social situation-dependent condition, characterised by persistent and exaggerated fear of embarrassment or humiliation in front of others. [2] It is among the most prevalent of anxiety disorders in children and adolescents, and can be significantly distressing and debilitating to its sufferers, causing social and academic impairment resulting in isolation, school avoidance and refusal. [2,3] Some studies have even shown a more serious side to this condition: anxiety disorders, including SP, are associated with increased risk of suicide attempts and deliberate self-harm. [4,5]

Existing literature found that family functioning is not associated with SP, but the persistence of SP in young people is greater when family functioning is dysfunctional. [6-8] Furthermore, parents of children with SP are likely to suffer from SP themselves, [6-8] there is an emerging association between SP and Bipolar Disorder (BPAD), while comorbid alcohol abuse in patients with BPAD and co-morbid SP seems to be recognised. [9-11] Interestingly, to date, there are no replicated findings about the impact of parental relationship factors on SP specifically.


The aim of this study is to investigate the potential risk and resilience factors in children with SP in the domains of family functioning, parental psychopathology and parental relationship.  The McMasters Family Assessment Device (FAD), Hopkins Symptom Checklist (HSCL) and Spanier Dyadic Adjustment Scale (DAS) were used to explore these three respective domains.


The hypotheses that the research addresses are 1) that family functioning between the SP and TD groups would not differ; 2) that parents of children with SP would show features of SP and other anxiety disorders and 3) that parental relationship factors would not have a clear association with SP compared to TD young people.


This research represents a cross-sectional study and was conducted at the Academic Child Psychiatry Unit (ACPU), Royal Children’s Hospital (RCH) in Melbourne. The ACPU is a clinical research unit that provides comprehensive, standardised assessments and treatment for children and adolescents with internalising and externalising disorders. Prior to the assessments, informed consent was obtained from the parents and children, and a consent form was signed. The data used in the analysis were obtained from standardised questionnaires and structured clinical interviews completed by the parents and young people.

An ethics approval was not required for this paper as both the data analysis and the questionnaires used in this research did not involve the use of identifying information. In addition, the questionnaires utilised for the data are part of the full standard assessment that all patients referred to the ACPU are required to undertake as part of their management. Furthermore, this research project is not part of a Doctoral or Master’s degree.

Family Functioning

In order to assess family functioning, the McMasters Family Assessment Device (FAD) was used. Devised in the 1980s by Epstein and colleagues, the FAD described seven aspects of family functioning through a 52-item questionnaire: problem solving, communication, roles, affective responsiveness, affective involvement, behaviour control and general functioning. [12] The selection of responses for each item ranged from 1 to 4, where 1 = strongly agree, 2 = agree, 3 = disagree, 4 = strongly disagree. [13] The positively oriented items were then recoded and the total score could range from 12 to 48, where higher scores represent better functioning. [13]

Parental Psychopathology

To measure parental psychopathology, the 58-item Hopkins Symptom Checklist (HSCL), a self-report symptom inventory, was utilised. It was scored on parental distress from 1 to 4, where 1 = not at all and 4 = extremely, and it was reported from the five symptom dimensions of somatization, obsessive-compulsive, interpersonal sensitivity, depression and anxiety. [14] The outcome of the survey was in the form of raw data, i.e. mean factor scores and standard deviations, calculated using average-unit weight methods, which made it better geared towards use in clinical research. [14]

Parental Relationship

The Spanier Dyadic Adjustment Scale (DAS) is a 32-item, widely used measure of relationship quality between couples. [15] For the purpose of this study, the abbreviated seven-item version of this instrument, which has shown good internal consistency and is deemed psychometrically sound, was used. [16] The DAS-7 consists of six-point Likert-type scales with end-points of “always agree” to “always disagree” or “all the time” to “never”. [16] The last item on the questionnaire rates relationship satisfaction on a seven-point scale, with end-points of “extremely unhappy” to “perfectly happy”. [16]

Statistical Analysis

Age, social adversity status (SAS) and full-scale IQ (FSIQ) were analysed using univariate analysis of variance, while gender was controlled using the chi square test.  The HSCL, FAD and DAS variables were analysed using univariate analysis of covariance, controlling for SAS and FSIQ.  Partial eta squared was used to ascertain effect sizes for variables that differed between the groups.  The value at which a sample is considered to be clinically significant or large, was set at η2 ≥ 0.10.


The 69 children diagnosed with SP and 129 TD children were identified using the Anxiety Disorders Interview Schedule for Children (A-DISC), which is a semi-structured interview conducted by clinically-trained interviewers. [17] The A-DISC comes in a parent (A-DISC-P) and child (A-DISC-C) form and is designed specifically to diagnose anxiety and other related disorders in individuals from 6-16 years of age. [17] Based on the parent and child account of the most distressing or interfering symptoms, the children are given a principle diagnosis and any other diagnoses fitting the criteria, as determined by the A-DISC. [17]   Patients with Full Scale IQ less than 70, and children living away from their parents were excluded. Patients with any coexisting DSM-IV-TR Axis I diagnosis were also excluded.

The SP and TD groups did not differ in their age or gender:  mean age of the children with SP was 11.01 while the mean age of the TDP was 10.50 years. Out of the experiment group, 40 of them were males and 29 females. Similarly there were more boys in the control group at 70, compared to girls, of which there were 53.

Family functioning

There were no clinically meaningful family functioning differences between the families of children with SP and the TD young people. This was based on scores of η2 = 0.06 for general functioning, η2 = 0.02 for problem solving, η2 = 0.03 for communication, η2 = 0.03 for roles and η2 = 0.03 for behaviour control, all of which are not clinically significant.

This suggests that families from both groups were able to effectively solve problems together and communicate, from a clinical standpoint. Furthermore, the results implied that the established roles and execution of those roles within families of either group were not dissimilar. Also, the way in which the expression and maintenance of behavioural regulation is achieved in the two groups was not different from a clinical perspective.

Parental psychopathology

The data revealed some interesting results in this regard, supporting previous literature that traits of anxiety are significantly present in parents of socially phobic children (F = 16.62, p < 0.0005, η2 = 0.10). Furthermore, it was found that parents of the control group displayed symptoms of an obsessive-compulsive (F = 20.08, p < 0.0005, η2 = 0.12) and depressive (F = 22.01, p < 0.0005, η2 = 0.13) nature. In addition, the effect size of the total HSCL score between the groups was η2 = 0.14.

This demonstrated that parents with children with SP also tended to have manifestations of anxiety, e.g. restlessness, nervousness, tension or even somatic signs like trembling. Moreover, these individuals tended to experience the presence of unwanted thoughts, impulses or actions more often than their counterparts. Interestingly, parents of SP children also appeared to suffer from more dysphoria, anhedonia, avolition and hopelessness than parents of the control group. Overall, the data showed that parents of socially phobic children seemed to have more symptomology of mental health problems than parents with TD children.

Parental relationship

Contrary to the hypothesis on parental relationship, the effect size of the total DAS scores of the two groups proved to be η2 = 0.11. Additionally, there were clinically significant problems with the happiness in the relationship (F = 20.41, p < 0.0005, η2 = 0.14) and ability of spouses with SP children to work together (F = 22.62, p < 0.0005, η2 = 0.15) compared to the control group.

This non-hypothesised result suggested that in families with children with SP, the relationships between the parents tended to be more strained, and they did not often collaborate on projects together.


In general, the results of the data analysis were largely similar to the hypotheses put forth at the beginning of this paper. As supported by Knappe and colleagues in both their 2009 publications, family functioning was not associated with a risk of having offspring with SP. Earlier studies by Lieb et al. nearly a decade before also agreed that there was no connection between a child with SP and family functioning.

They did, however, discover that other parental factors, which were outside the scope of the measures used in this project, were associated with greater persistence of SP in children with the diagnosis. For instance, in cases where parents also had SP, negative parental rearing styles like parental overprotection coexisted (DSM-IV threshold SP: Beta = 0.23, T = 2.06, p = 0.043; at least sub threshold SP: Beta = 0.22, T = 2.07, p = 0.042). [8] In situations where there was an absence of disorders in parents, parental rejection (Beta = -0.42, T = -2.18, p = 0.032) also caused the persistence of SP in their offspring. [8] Furthermore, it was noted that, when families were dysfunctional in their functioning, SP tended to be more persistent in the children. [8]

According to the data produced in this study, parents of children with SP tend to have traits of anxiety and obsessive compulsive disorders themselves. Interestingly, the results also showed that a clinically significant portion of these also suffered from depressive symptoms.

It is well known in the literature that parents with SP themselves are at greater risk of having offspring with SP. [6-8] One study supported the findings of this paper, showing the risk of children developing SP is greater when their parents have SP (OR =3.3, 95% CI: 1.4-8.0), other anxiety disorders (OR =2.9, 95% CI: 1.4-6.1), depression (OR =2.6, 95% CI: 1.2-5.4), and even alcohol use disorders (OR =2.8, 95% CI: 1.3-6.1). [7]

This was not the first time alcohol abuse has been associated with SP. Studies by Perugi et al. found that patients with SP and co-morbid Bipolar Affective Disorder Type II (BPAD II) tended to develop alcohol abuse problems. [10] In that situation, however, they argued that the co-existence of BPAD and SP led to protracted anxiety in social situations, which may have explained their increased susceptibility to using alcohol as a social lubricant. [10-11]

Future research should seek to uncover whether the symptoms experienced by the parents are a direct result of raising children with SP, or whether their own psychopathology has contributed to their children’s condition.  Longitudinal study designs are needed.

It was hypothesised that the parental dyad would not be affected as a result of having a child with SP, due to the fact that SP, like many anxiety disorders, are internalising conditions. However, in this study these individuals ranked lower in relationship satisfaction and working on joint projects together. One explanatory theory could be that behavioural difficulties in children with SP, such as school refusal and poor academic performance, indirectly cause discord in the relationship of their parents. Conversely, a troubled parental relationship could potentially exacerbate or even contribute to symptoms of SP that their child.

Although no prior studies have been conducted exploring the use of the DAS as a parental relationship measure, the findings are not unreasonable. A study in 1997 by Friedman et al., which examined adaptive functioning in the families of patients with psychiatric disorders, agreed with this. Their research found that, regardless of diagnosis, having a family member in an acute phase of a psychiatric illness was a significant stressor and put them at risk of poor family functioning. [18]

It may be reasonable to conclude then, that having an offspring with SP puts stress on the family as a whole, and can therefore lead to difficulties within the parental relationship. For instance, the demands of caring for a child with SP in addition to other responsibilities may result in less time spent together as a couple, and hence less time spent working together on projects. Given enough time, this may lead to relationship dissatisfaction. Ideally, future research will recreate or produce more modern data looking into this area, allowing for better interpretation.

Relevance to general practice

As alluded to earlier in this paper, there is a darker side to suffering from SP: namely the risk of suicide and self-harm. Even if one disregards this aspect of the condition, it is undeniable that an individual’s development will be impaired if they are unable to fully participate with their peers socially and academically when growing up. In addition, this research supports the fact that the parents and family unit should not be forgotten when it comes to managing SP in young people. [1]

One of the more effective treatments for SP is Cognitive Behaviour Therapy (CBT). [3,19] In addition to treating SP in children, CBT is also useful in managing adult depression and anxiety disorders. [19] Also within the scope of CBT is dealing with issues related to marital distress. [19] CBT is a type of talking-therapy where a person’s emotions, thoughts and behaviours as linked to particular circumstances e.g. social situations, and negative thought patterns are challenged. [19]

While traditionally seen as a time consuming form of psychotherapy in the GP context, a recent article by Harden encourages GPs to reconsider. [19] She argues that CBT is among the least consuming of psychological therapies, due to its highly structured nature. [19] Furthermore, where CBT was once the domain of psychologists and psychiatrists, Harden outlines several resources for GPs to undergo training in basic CBT techniques, which will enable them to utilise this skill. [19]

Post-training, GPs should be well-equipped to handle the milder forms of SP and family dynamics, and still retain their ability to refer complex cases to specialists. [19] Moreover, they can serve as a bridge for more complex patients who are waiting for specialist appointments. [19] These GPs can gain satisfaction from enabling their patients to develop problem solving techniques, take more responsibility and make better choices. [19] As an added bonus, GPs trained in psychotherapy now receive greater rebates from the government as an incentive to participate in mental health care. [19]

Exposure therapy is another form psychotherapy which effectively manages SP, which GPs are able to execute. [2,20] This behavioural intervention, which incorporates activity scheduling, graded task assignment, distraction and relaxation, can be easily learned by both GPs and patients to a level of competence comparable to treatments conducted by mental health specialists. [2]

Another way to manage SP is using drug therapy, e.g. sertraline with or without psychotherapy. [20] Blomhoff and colleagues found that sertraline was one of more ‘GP-friendly’ psychiatric drugs, owing to its effectiveness and tolerability. They recommended a blend of sertraline and exposure therapy to manage SP in general practice, the latter more so in patients unsuitable for drug treatment or who do not respond to sertraline alone. [20]


In summary, although family functioning per se is not associated with an increased risk of SP in children, the presence of dysfunction can lead to protracted SP. Moreover, the stress of having a family member with a mental illness can impact on the parental relationship, causing problems. This may or may not be related to the parents of young people with SP displaying greater symptoms of anxiety, obsessive-compulsiveness and depression. These interplaying factors make it necessary to consider both the parents and child, when constructing a management plan.

The field of primary care is well-equipped to aid with the management of patients with SP and their families through the use of psychotherapies e.g. CBT and exposure therapy, as well as medications e.g. sertraline. This will be extremely beneficial due to the debilitating and sometimes serious nature of this problem.

Future research should be geared towards producing more modern data and exploring the areas of parental relationship and parental psychopathology in the context of SP, in more detail.


To Associate Professor Alasdair Vance – Head of the Academic Child Psychiatry Unit at The Royal Children’s Hospital. Your guidance, encouragement and support were integral to the completion of this project.

Conflict of interest

None declared.


S de Menezes:


[1] Sanci L, Vance A, Haller D, Patton G, Chanen A. Common mental health problems in adolescents. In: Blashki G, Judd F, Piterman L, editors. General Practice Psychiatry

[2] Haug TT, Hellstrøm K, Blomhoff S, Humble M, Madsbu H-P, Wold JE. The treatment of social phobia in general practice. Is exposure therapy feasible? Family Practice. 2000 Apr;17(2):114-8

[3] Baer S, Garland EJ. Pilot study of Community-Based Cognitive Behavioral Group Therapy for adolescents with social phobia. Journal of the American Academy of Child and Adolescent Psychiatry. 2005 Mar;44(3):258-64.

[4] Nepon J, Belik S-L, Bolton J, Sareen J. The Relationship between anxiety disorders and suicide attempts: Findings from the epidemiological survey on alcohol and related conditions. Depression and Anxiety. 2010 Sep;27(9):791-8

[5] Chartrand H, Sareen J, Toews M, Bolton JM. Suicide attempts versus nonsuicidal self-injury among individuals with anxiety disorders in a nationally representative sample. Depression and Anxiety. 2012 Mar;29(3):172-9

[6] Lieb R, Wittchen H-U, Hofler M, Fuetsch M, Stein MB, Merikangas KR. Parental psychopathology, parenting styles and the risk of social phobia in offspring: A Prospective Longitudinal Community Study. Archives of General Psychiatry. 2000 Sep;57(9):859-66.

[7] Knappe S, Lieb R, Beesdo K, Fehm L, Low NCP, Gloster AT, et al. The role of parental psychopathology and family environment for social phobia in the first three decades of life. Depression and Anxiety.2009;26(4):363-70 .

[8] Knappe S, Beesdo K, Fehm L, Ho¨fler M, Lieb R, Wittchen H-U. Do parental psychopathology and unfavorable family environment predict the persistence of social phobia? Journal of Anxiety Disorders.2009 Oct;23(7):986-94.

[9] Pini S, Dell’Osso L, Amador XF, Mastrocinque C, Saettoni M, Cassano GB. Awareness of illness in patients with bipolar I disorder with or without comorbid anxiety disorders. Australian and New Zealand Journal of Psychiatry. 2003 Jun;37(3):355-61.

[10] Perugi G, Frare F, Madaro D, Maremmani I, Akiskal HS. Alcohol abuse in social phobic patients: is there a bipolar connection? Journal of Affective Disorders. 2002 Feb;68(1):33-9.

[11] Perugi G, Frare F, Toni C, Mata Bn, Akiskal HS. Bipolar II and unipolar comorbidity in 153 outpatients with social phobia. Comprehensive Psychiatry. 2001 Sep-Oct;42(5):375-81

[12] Epstein NB, Baldwin LM, Bishop DS. The McMaster Family Assessment Device. Journal of Marital and Family Therapy. 1983 Apr; 9(2) 171–180

[13] Georgiades K, Boyle MH, Jenkins JM, Sanford M. A multilevel analysis of whole family functioning using the McMaster Family Assessment Device. Journal of Family Psychology. 2008 Jun;22(3):344-54

[14] Derogatis LR, Lipman RS, Rickels K, Uhlenhuth EH, Covi L. The Hopkins Symptom Checklist (HSCL): A self-report symptom inventory. Behavioural Science. 1974 Jan;19(1):1-15

[15] Graham JM, Liu YJ, Jeziorski JL. The Dyadic Adjustment Scale: A reliability generalization meta-analysis. Journal of Marriage and Family. 2006; 68:701-717.

[16] Hunsley J, Best M, Lefebvre M, Vito D. The seven-tem short form of the Dyadic Adjustment Scale: Further evidence for construct validity. American Journal of Family Therapy. 2001;29(4):325-335.

[17] Lyneham H, Abbott MJ, Rapee RM. Interrater reliability of the Anxiety Disorders Interview Schedule for DSM-IV: Child and Parent version. Journal of the American Academy of Child and Adolescent Psychiatry. 2007; Jun;46(6):731-6.

[18] Friedman MS, McDermut WH, Solomon DA, Ryan CE, Keitner GI, Miller IW. Family functioning and mental illness: A comparison of psychiatric and nonclinical families. Family Process Journal. 1997Dec;36(4):357-67.

[19] Harden M. Cognitive Behaviour Therapy: Incorporating therapy into general practice. Australian Family Physician 2012 Sept;41(9):668-671

[20] Blomhoff S, Haug TT, Hellstrøm K, Holme I, Humble M, Madsbu HP, et al. Randomised controlled general practice trial of sertraline, exposure therapy and combined treatment in generalised social phobia. The British Journal of Psychiatry. 2001 Jul;179:23-30

Review Articles Articles

The benefits associated with male HPV vaccination in Australia

Background: Human papillomavirus (HPV) is a family of highly contagious sexually transmitted viruses which are associated with the development of genital warts and certain HPV related cancers in males and females. After conducting a cost-effective analysis, the Australian Government has decided to expand the school based female only HPV vaccination program to include males commencing in 2013. Methods: A search of Ovid MEDLINE, The Cochrane Library, Google Scholar, BMJ Journals, and JSTOR was undertaken. Discussion: HPV vaccination has proven to have a high safety profile with sustained efficacy rates. Male vaccination will not only offer immunity to its recipients but also provide indirect protection to both sexes and high risk groups through herd immunity. The included high risk HPV strains 16 and 18 are associated with more than 70% of cervical cancers, 80% of anal cancers, 25% of penile cancers and 31% of oropharyngeal cancers worldwide. The quadrivalent vaccine also covers HPV 6 and 11 which are responsible for 90% of genital warts. Conclusion: Robust monitoring and surveillance systems are in place which will enable Australia to quantify the impacts of HPV vaccination in the future. Models show that the rates of HPV infection will further reduce by an additional 24% in 2050 compared to female vaccination alone, if vaccination rates for boys reach the same levels attained by girls in 2011. This will result in a significant decrease in the clinical burden of HPV-related diseases, the associated costs of treatment, and the psychological trauma which often accompanies the diagnosis of an HPV-related condition.


Human papillomavirus (HPV) is a highly contagious family of viruses with over 150 distinct genotypes. [1] The virus infects the squamous epithelium in both males and females, with over 40 genotypes affecting the anogenital region. [2-4] HPV is usually a transient, asymptomatic infection which is transmitted through skin-to-skin contact associated with sexual activity, and the risk of infection increases with a greater number of sexual partners. [2-5] HPV is also the most common sexually transmitted infection (STI), [6] with up to 80% of people being infected with at least one type of genital HPV in their lifetime. [3,7,8]

There is a proven association establishing the relationship between persistent HPV infection and the development of pre-cancerous (CIN) and cancerous lesions in females. [7] Australia was the first of many countries to create a National HPV Vaccination Program for females, and has been providing the school based HPV vaccination to 12-13 year old girls since 2007. [9,10] Males are expected to join their female counterparts commencing in February 2013. [11,12]

Australia provides this vaccination in the form of the quadrivalent Gardasil® vaccine which covers four types of HPV (6, 11, 16 and 18). [8] In women, although there are many ‘high risk’ types, HPV 16 and 18 alone are associated with 70% of cervical cancers, [2,3,13] and 32% of vaginal cancers worldwide. [14] In men and women, those two types also contribute to over 80% of anal cancers, 24% of oral cancers, and 31% of oropharyngeal cancers. [6,14] Furthermore HPV 16 and 18 account for 90% of all HPV attributable male cancers. [5]

The other two HPV types covered by the quadrivalent vaccine, HPV 6 and 11, are associated with 90% of genital warts and 100% of juvenile onset recurrent respiratory papillomatosis (RRP) cases, resulting in a severe respiratory condition. [14] Recent studies also reveal that more than 4% of all cancers worldwide may be caused by HPV. [15,16]

On the back of such evidence, the Australian Government has announced the introduction of the quadrivalent HPV vaccination for males in the 12 -13 age group, with a catch-up program for males aged 14-15 years at school. [11,12] Early data show that 73% of females in the 12-13 age group received the full course of three doses (Figure 1). This level of coverage is significantly higher than the levels in the catch up programs where the lowest level is 30% in the 20-26 year old age group. Therefore, introducing an immunisation program for boys is a significant move towards preventing the many HPV attributable cancers and genital warts by accelerating coverage and the levels of herd immunity against HPV.

Therefore, the aim of this article is to examine the evidence which exists globally in supporting HPV vaccination and to identify any additional benefits routine male vaccination may provide. The article will also consider high risk population groups, the cost effectiveness of widespread HPV vaccination and the long term monitoring goals for the Australian vaccination program.


The review of the literature was undertaken through a search of Ovid MEDLINE, The Cochrane Library, Google Scholar, BMJ Journals, and JSTOR. The search aimed to find original research articles, reviews, case studies, and opinion pieces that related to HPV vaccinations and the spread of sexually transmitted infections. The terms used in our search ensured we reviewed a broad range of relevant studies. These terms were: ‘human papilloma virus’, ‘males’, ‘quadrivalent’, ‘vaccine’, ‘sexually transmitted disease’, ‘cervical cancer’, ‘penile carcinoma’, ‘herd immunity’, ‘genital warts’, ‘cost effectiveness’ and ‘pap smear’. We also sought to review the ‘grey literature’, and therefore searched a broad range of internet sources, including government websites. These were accessed for up-to-date information on the HPV vaccination program, the cervical screening program, and relevant legislation. The studies were limited to those published in the English language after the year 2000.

Using the methodology described above, 63 articles and documents found during the search were selected for consideration. After individually analysing all the identified documents, 39 publications were selected for inclusion in the final review with preference given to more recent publications and those with data which could be applied to the Australian program. Of these remaining publications, 16 were original research articles, 15 were review articles, 6 were Australian Government reports or legislation, 1 was a professional communication, and 1 was a media release. The remaining 24 publications were excluded as they were assessed as not relevant to the Australian program.


Evidence for HPV vaccination in men

HPV vaccinations worldwide has revealed no major safety concerns, [5] and recent clinical trial data show that the safety profile for males is the same as for females. [18] The most commonly reported side effects have been mild and include fever, nausea and localised injection site pain. [19] Furthermore, there have been no reported deaths that are directly attributable to the vaccine. [5,20]

Currently, only the quadrivalent vaccine has demonstrated protective effects for males in clinical trials. [18] Boys vaccinated with the quadrivalent vaccine have the same seroconversion rates as girls, which is as high at 99%. [21] In addition, the current implementation of the HPV vaccination program for girls in Australia does not have full coverage. [8] Vaccinating males will provide indirect protection to the targeted females in the school HPV vaccination program who were not fully vaccinated, by increasing herd immunity. [8] This protection is vital because there is good evidence that vaccines which include HPV 16 and 18 prevent persistent HPV infections and precancerous cervical, vulvar, and vaginal lesions in females. [14]

Therefore, the inclusion of males into the HPV vaccination program will provide them, and possibly their unvaccinated sexual partners, with protection from HPV. [14] This will also result in higher levels of herd immunity, which refers to the protective effect offered to the unvaccinated and susceptible population by having high rates of acquired immunity in the vaccinated population. [22] This phenomenon acts to limit the cases of transmission and the reservoirs of disease. One example of herd immunity is the widespread vaccination of males against rubella even though the virus is of little clinical significance in males. This vaccination program in Australia has led to a significant reduction in the transmission of rubella to susceptible pregnant females and the subsequent development of congenital rubella syndrome. [6,23]

Male vaccination not only provides direct protection to its recipients, it also further reduces rates of transmission [5] and provides indirect population benefits to protect members of both sexes through herd immunity. [24] A retrospective seminal study across Australia compared rates of genital warts before and after female vaccination and post immunisation in the 2004-2009 time period. Results demonstrated a 59% decrease in genital warts in age matched females who were eligible for free vaccination and a corresponding decrease of 28% in heterosexual males in the same age bracket who were ineligible for free vaccination. [25] These trends were supported by another Melbourne study which reported the near disappearance of genital warts in heterosexual females and males under 21 years of age. [26] These studies provide early evidence of the benefits of vaccination providing herd immunity which has reduced the clinical burden of genital warts, the high costs of treatment, [27] and the psychological impact associated with the condition. [28,29]

However, the impact of genital warts in the Australian community can be further reduced. One model of HPV transmission suggests that if vaccination rates for boys reached the same 73% level attained by girls in 2011, then by 2050 the vaccination of boys would have prevented an additional 24% of new HPV infections. [5] Other mathematical models suggest that while vaccination of 12 year old girls alone would reduce the incidence of genital warts by 83% and cervical cancer by 78%, including boys in the vaccination program would reduce the incidence of genital warts by 97% and cervical cancer by 91%. [30]

The vaccination of males would not only help the female population, but would also reduce the disease burden for males. This was demonstrated in study of 4065 healthy boys which demonstrated a clear reduction in the development of external genital lesions. [18] One month after the boys received their third and final vaccination,
seroconversion for all four types of HPV had occurred in 97.4% of boys, with an additional 1.5% of the cohort seroconverting for only three types of the four. [18] Vaccination was shown to reduce the incidence of external genital lesions, due to infection with HPV types 6, 11, 16 and 18, by 90.4% in the per-protocol population. [18]

Nonetheless, the lack of long term data means there is currently no clinical evidence demonstrating a reduction in HPV related male cancers after vaccination. However, two of the quadrivalent vaccine types, HPV16 and HPV18, are responsible for 90% of all HPV attributable cancers in men. [5] Therefore, since the quadrivalent vaccine has demonstrated a reduction in high grade cervical lesions in women, [8] there is an expectation that vaccination will have the same effect for cancers in men. [8,31] Worldwide, HPV types 16 and 18 are associated with over 80% of anal cancers, 25% of penile cancers [6,14,15] and 31% of oropharangeal cancers, [14] so the potential for benefit is significant.

In addition, with the reduced rates of smoking, HPV is becoming an increasingly significant cause of oropharyngeal cancer. [32] Most of the oropharyngeal cancers in non-smokers are caused by HPV infections, and the majority of patients are men. [32] Vaccinating women alone is less effective in reducing the rates of infection and both males and females need to be vaccinated for maximal benefit. [22] Male HPV vaccination is expected to lead to a reduction in the oncogenic HPV prevalence in the community and together with female HPV vaccination, it may reduce the incidence of HPV related oropharyngeal cancers in non-smokers. [32]

However, the lack of long term data means that it is uncertain how long immunity will last before a booster is necessary. Current followup studies suggest that the vaccine remains effective in a population vaccinated 8.5 years ago. [8] Further follow-up is necessary to ensure that the vaccine continues to be effective over longer periods of time.

Populations at risk

There is poor uptake of the National Cervical Screening program among women of Aboriginal and Torres Strait Islander (ATSI) background. [7] Among other factors, this poor uptake is one of the reasons why they have twice the risk of developing cervical cancer and their mortality rate is 5 times higher than the general population. [7]

Including boys in the vaccination program has been modelled to further decrease the rates of genital warts and cervical cancer beyond that which would be attained by female vaccination alone. [30] However, the argument has been made that if there is sufficient uptake of vaccination among girls most males would eventually be protected through female vaccination alone. [22] This argument has merit if the vaccination rates among girls are extremely high, but it assumes transmission only through heterosexual relationships. One of the populations at highest risk of HPV infection is men who have sex with men (MSM). [5] This population acquires little benefit from the current HPV vaccination program, [5] and logic suggests that the HPV infections would persist in this population even with immunisation of all females. MSM are at 30 times the risk of anal cancer when compared with other men. [5] As 90% of anal cancers are associated with HPV, [6] the vaccine has the potential to provide significant benefits for this high risk population. However, it would be difficult on many levels to target the MSM population for immunisation. Targeted immunisation would need to reach MSM at an early stage of sexual activity, but at that time many may be reluctant to disclose their sexual orientation due to a fear of stigma. [5] Therefore, a program of routine male vaccination solves the need to target this group specifically by immunising all young boys prior to sexual debut.

Another population which is at higher risk of HPV infection is men and women with impaired immunity such as organ transplant recipients. [6] Although heterosexual males with impaired immunity may have some protection from the HPV vaccination program for girls, [5,30] heterosexual females and MSM with impaired immunity would not receive the same degree of protection. Immunosuppressed populations are more likely to develop persistent infections which progress to dysplasia and cancer. [6] Wide vaccine coverage would ensure high levels of immunity in the community that should lower the risk of HPV transmission to all high risk groups.

Cost effectiveness

The immediate costs of implementing and monitoring the female-only HPV program was reported in 2007 to be AU$103.5 million over five years. [33] The addition of males to the program added AU$21.1 million over four years in 2012. [12] Although the Australian Government has approved the addition of males to the HPV vaccination program, the cost effectiveness of such a move is still debated in Australia and worldwide. [5,14,34,35]

Some studies have reported that the vaccination of males is not cost effective when compared to female vaccination alone. [5,14,34,35] These reports were made with the commonly used consideration that an incremental cost-effectiveness ratio (ICER) of greater than US$50,000 per quality-adjusted life-year (QALY) is not considered costeffective. [5] However, other studies have shown that the equation becomes much more favourable when protection against all HPV related diseases affecting men and women are included, as that drops the ICER to US$25,664 per QALY. [36]

Although the Australian Government has not released their analysis on the cost effectiveness of including males in the HPV vaccination program, past experience suggests that anything below an ICER of less than AU$60,000 per QALY is generally accepted. [5]

The cost models can only provide an estimation of the impact of HPV not be apparent for some time. This is due to the time interval between HPV infection and the development of cancer. [3,36] However, the rates of genital warts, which are more prevalent and develop more quickly, are already decreasing. [25,26]

The cost per person of vaccination may seem high initially but when the cumulative effects of herd immunity are taken in to account the equation becomes more favourable. [24] In addition, the benefits of HPV vaccination are many, and cost effectiveness studies should take into account the psychosocial benefit, the reduction in the clinical burden of disease, as well as the reduced costs of treating the various presentations of HPV related cancers and genital warts. For example, the treatment of genital warts alone is estimated to cost AU$14 million annually in Australia. [27]

Future research and monitoring

Monitoring the efficacy, safety and the impact of HPV vaccination is an important step in measuring the effectiveness of the vaccination program and in guiding future policy. There are some challenges in vaccine program monitoring due to the long time interval between HPV infection and the development of HPV related cancers, as well as the asymptomatic and transient nature of infection. [3,37] However, the setup of the National HPV Vaccine Program Register (NHVPR) is a key step towards collecting vaccine coverage and dose status data of the target population, as well as collecting basic demographic data of recipients across Australia. [33] This information is only collected with prior consent and enables administrators to match accurate data collected from different registers to individuals. This allows them to run follow up programs to send reminders for missed doses or for boosters if they are required in the future. These data, combined with the information collected by state based cervical cytology registers and the Australasian Association of Cancer Registries provides a powerful tool to quantify the impact of the vaccination program on the incidence of cervical and other HPV related cancers in the long term.

Information regarding the safety of the vaccine and any associated adverse effects is collected by the Medicines Safety Monitoring office of the Therapeutic Goods Administration. [20] However, currently there are no nationally funded programs which monitor HPV genotypes in the general population and the vaccinated group. This could be a method to monitor HPV prevalence in the future or a way to screen for HPV related cancers. [7] The impact of vaccination on targeted groups such as MSM and ATSI Australians should also be monitored to evaluate the impact of the prophylactic vaccine on these high risk groups.


The aim of the Australian immunisation program is to introduce immunity against the included HPV types before the commencement of sexual activity through a prophylactic HPV vaccine. Through this program, males and females in the pre-adolescent age group are immunised before their sexual debut (which usually creates a peak in incidence of HPV). [38]

Although the use of barrier contraception such as condoms, and male circumcision may offer some protection, any skin-to-skin contact during sexual activity can result in the transmission of HPV. [3] Currently, HPV vaccination is the only reliable and realistic method of primary prevention of HPV infection. It has proven to be safe with a high efficacy and minimal side effects. [20,21] The vaccination has the potential to significantly reduce the clinical burden of HPV-related disease, the associated high costs of treatment, and the adverse psychological impact which can be caused by the diagnosis of a HPV related disease. [28,29]

Male vaccination not only provides benefits to its recipients but also provides indirect benefits to females and the wider population. This will result in accelerated herd immunity and increase the protection offered to susceptible and high risk groups such as unvaccinated females, MSM, immunocompromised individuals, and members of the ATSI community.

Furthermore, the introduction of HPV vaccination for all young males and females will further Australia’s contribution to the prevention of HPV associated diseases worldwide and provide invaluable data describing the long term effects of HPV vaccination. For a population based primary prevention program to be successful there needs to be strict and persistent surveillance and monitoring of its implementation. Currently, Australia has no national program for the surveillance of HPV or genital warts, although it has setup the NHVPR, which monitors the population vaccination coverage. In collaboration with the PAP test and cancer registries, the information collected through this register should provide invaluable data on the impact of HPV vaccination in females. This monitoring will be extended in 2014 to include males, providing a robust data set enabling the measurement of the impact of HPV vaccination on the incidence of HPV related cancers in the coming years.

Conflict of interest

None declared.


We would like to thank Dr. Richard Mayes and Dr. Catherine Foley for their assistance and support.


M Boulat:
A Hatwal:


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Feature Articles Articles

Emergency medicine in Australian medical student education

“The best way to predict the future is to invent it.” Alan Kay


As the coalface of Australian healthcare, Emergency Medicine (EM) faces the growing healthcare challenges of the wider community. Today, these challenges form a unique ‘triple whammy’ – overseeing the implementation of the National Emergency Access Target (NEAT) or “4-hr rule”, in an effort to manage access block and emergency department overcrowding as a result of the increased care needs of an ageing population, whilst at the same time with limited resources attempting to maintain the quality of education and training of a burgeoning junior medical workforce. [1,2]

Amidst this conundrum, medical student EM education may sometimes be left in the shadows. [3,4] The unique arena of the emergency department with its volume, breadth and variety of undifferentiated patient cases not only provides countless learning opportunities for medical students but also allows them to contribute to healthcare teams in practical and meaningful ways. This ranges from assisting in initial assessments, to performing indicated procedures, to formulating discharges, and even research involvement. [5,6] All of which are useful and valuable skills favoured upon in a junior medical doctor and reduces the workload of the supervising team. [7-9] While some may argue that the general wards offer similar opportunities, the increasing attempts in improving efficiency and subspecialising medicine have led to the bulk of diagnostic and therapeutic interventions to be conducted in the emergency departments prior to acceptance by inpatient units. [4]

Students themselves find EM rotations extremely valuable, with many practical benefits for their future medical careers. [10] However, the already hectic and stressful EM work environment, coupled with enhanced time pressures from NEAT, increasing numbers of interns needing to complete an ED term, and the significant teaching and supervision requirements within EM departments may prove to be hurdles that limit the chances for medical students’ education. [11]

Thus, it may be prudent to re-examine this issue of our workforce challenges and to re-assess  medical student education.

  1. Could added investment in extension and evaluation of EM to medical students pique their interest in a future EM career?
  2. Would an increased focus on EM teaching better equip and innovate Australia’s future healthcare workforce?

Why is EM important in medical student education?

As a population-based specialty, EM education offers medical students a glimpse into the domain of public health. Patients present with illnesses and injuries that have high population prevalence, and presentations vary even across times of the day. Students are therefore exposed to a dynamic socioeconomic, cultural and demographic case mix. This serves to broaden not only the variety in conditions that students would see within an EM rotation, but also widens their perspectives on pertinent issues affecting different age groups in the Australian healthcare setting.

EM also provides an opportunity to learn about pre-hospital care, including co-ordinating ambulance and paramedic transfer services, retrieval, wilderness and disaster medicine.  Students encounter clinical scenarios they would not otherwise see such as occupational and environmental health, toxicology and trauma, and are also exposed to accident and injury surveillance, treatment and prevention.

EM has unique content areas that form the foundation of medical student training. In fact, EM exposure is seen as a form of clinical training assurance and a measured criterion for both students and junior doctors to be work-ready, and is considered essential and highly valuable as a core intern term in all states around Australia. [7]

With each undifferentiated presentation, students are encouraged to complete a focused history and examination, consider emergency interventions and prioritise differential diagnoses, rather than needing to pinpoint a correct diagnosis in a second. They then formulate streamlined investigation and management plans, and have opportunities to perform basic procedures which form part of the initial evaluation of many patients. Students can also receive positive feedback and critique from clinicians on their performance, and even observe and learn from their more senior colleagues in managing acutely ill patients. [4]

There are other unique benefits of students training in the ED environment. With the rollout of NEAT, clinicians may be increasingly pressured to make time-critical evaluations and decisions. Students would therefore not only be able to observe time and cost effective patient assessment strategies but also hone problem solving and task prioritisation skills. [12] The acute management of common ED presentations would be better appreciated as fewer patients stay in the ED for hours or days and are transferred to the wards within four hours. Furthermore, a minimum of 40% and up to 73.3% of patients within the ED are available for directed-learning purposed interaction with student doctors – a significantly higher percentage than inpatient wards. [4,13]

Many EDs now also contain short stay units (SSU) where patients requiring short admissions or periods of observation are managed. A multidisciplinary healthcare team is often involved in the care of these patients, and students are able to work with the team and are involved in allied health discussions and discharge planning meetings.

How can students learn more?


Medical students are usually not rostered on overnight shifts due to a lack of senior medical staff and thus inadequate supervision. A 24-hour rostering of students may be one way to combat the need for more placement opportunities, provided it does not overload junior medical staff. Elective night shits have already been occurring though there is no current data evaluating medical students’ learning during those specific shifts. Nonetheless, there would be benefit in providing observational exposure to a different case-mix of patients, especially in resuscitation situations, where students can play a more hands-on role during night shifts.


Simulation skills laboratories have been a proven tool in improving theoretical knowledge and procedural skills for medical students, especially in deteriorating patient or acute resuscitation scenarios. [14] These courses, along with other electronic resources can also be utilised for on or off-site learning. More traditional trauma training courses and more novel methods such as cadaver based simulation course for advanced emergency procedures have also proved useful in equipping medical students with basic and advanced procedural skills. [15]

Decision supports

Competency-based training including the use of logbooks and clinical pathways has been shown to improve quality of care in some areas of medicine. [16-18] Logbooks are currently used at various specialty training colleges including ACEM, and adoption for EM education can assist students to measure their abilities against a minimum standard. Medical diagnosis or treatment protocols or checklists can also guide students in developing a systematic approach to evaluating and treating various conditions.

How can students contribute more?

Previous research has shown the potential benefit that engaging medical students as paid assistants of the healthcare team can have on performance efficacy and workflow. Pilot projects have been tested in Germany and the USA. [8,9]

If introduced, a similar system within the EM departments where medical students assist in triaging patients, undertake basic procedures and complete preliminary paperwork alongside a nurse or rapid assessment clinician may expedite care and reduce waiting times for patients.  They could also aid in collating relevant medical information from GPs, specialists, residential care facilities and families. This would ease the paperwork burden for clinicians, improve efficacy of clinician-patient contact time and at the same time provide learning opportunities for students whilst collecting and synthesising information.

Medical students can also play an important role in academic aspects of EM. It is sometimes difficult for clinicians to allocate specific time for research whilst balancing patient care; thus students can assist in identification and recruitment of subjects, drafting of protocols and briefing of staff members on ongoing projects.

Where to from here?

The immediate challenges EM departments face should not deter EM clinicians’ involvement in training medical students for the future. [11] Rather, a collaborative effort with students to enhance EM learning will give future doctors a skillset applicable in any emergency scenario, regardless of specialty area.

As such, students’ feedback on EM rotations and learning techniques should be considered when planning EM curricula. Allocation of dedicated teaching time and educators along with adequate funding for implementation of various initiatives such as e-learning and simulation courses should also be made available for use.

Further research evaluating the current state of EM medical student education nationwide is crucial to identify key areas for improvement. Pilot projects testing novel ways such as those listed above to allow students to contribute to EM departments will also be beneficial to further evaluate innovative learning techniques.

Despite the added cost and effort required, EM training has proven invaluable for medical students and remains an essential part of their training. It is therefore highly recommended that EM continues to maintain a strong presence in medical students’ curriculum. [5]

Conflict of interest

None declared.


The authors would like to thank Dr Tony Kambourakis and Dr Simon Craig for their valuable assistance in guiding the development of this manuscript.


C Liew:


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