General Medicine

Epidemiology, Classification and Pathology of Pulmonary Hypertension (An interview with Professor Trevor J Williams, Clinical Director, Allergy, Immunology

and Respiratory Medicine, the Alfred Hospital, Melbourne, Australia)Last week a young new mother presented catastrophically ill to Professor Williams’ hospital in Melbourne. When Professor Williams started his career such a patient would have immediately been assessed and listed for urgent transplantation - with the hope that the patient would survive long enough to receive it. Due to the significant medical advances over The last decade, Professor Williams was able to offer this patient treatments which are effective to the extent that this patient will avoid transplantation now and hopefully for a long time into the future. Professor Williams takes time out to discuss the epidemiology, classification and pathology of this ‘nasty, proliferative disease, that untreated has a Prognosis often worse than metastatic breast cancer’. Why is it so important to have clear definitions in pulmonary arterial hypertension (PAH)? It is important that patients with PAH are diagnosed promptly in order that they can start on treatment early which has a positive impact on functional capacity and survival.There are numerous things to consider when making a diagnosis of PAH. In the elderly, trying to distinguish between pulmonary hypertension(PHT) secondary to left heart disease(particularly LV diastolic dysfunction) and PAH can be challenging. It is important to remember that PHT as seen on an ECHO is not PAH without further investigation including right heart catheter (RHC). It is therefore important to provide clear definitions of both conditions to support clinicians in diagnosis. What are the definitions of PHT and PAH? Pulmonary hypertension (PHT) is defined as: ‘abnormally elevated mean pulmonary arterial pressure measured at right heat catheter’. The WHO ‘Venice’ 2003 criteria, modified at Dana Point in 2008, provide the following guidelines of PHT: 14mmHg true normal; What has led to the change in the incidence of PAH? In adults, data on the incidence of PAH ranges from approximately 2-7 per million/per year; for children, this figure less than 1/million population however as < 25% of the whole population in the developed world are children this equates to approximately 2.8 per million/per year. There is certainly a sense that the disease is much more common than we first thought. Some data might suggest an increase in incidence; however, there is an increased recognition and diagnosis of PAH so whether there is a true increase in case numbers is very unclear. Females have a notably higher incidence/prevalence of PAH in paediatric and adult PAH but not neonatal. What has led to the increase in the prevalence of PAH? Current data suggests adult prevalence of approximately 15-55 cases per million population. The prevalence of PAH has certainly increased quite dramatically because instead of patients dying quite quickly, the treatments have been very effective at prolonging life. We find in a lot of other diseases that if you take an interest in a disease, diagnose and manage it properly,outcomes seem better. This leads one to question whether it is actually the new therapy that is making a difference, particularly in the absence of longer term randomised control trial data. In PAH, it appears that the new pharmacological interventions make the greatest difference; but a focussed approach in expert centres has likely contributed an increase in survival and therefore an increase in the prevalence of PAH. What are the implications of the increased prevalence of PAH? PAH is still an uncommon disease but there are many more patients living with PAH than we first thought. It is important that healthcare systems recognise the increasing prevalence and ensure appropriate education, infrastructure and resources are in place. Why is understanding the pathology in PAH so important? PAH is a disease that leads to extensive proliferation within the small blood vessels of the lung; it is not simply a disease characterised by constriction of vascular smooth muscle. PAH is a nasty proliferative lesion that requires treatment with targeted drug therapies. The proliferative nature of PAH has led some to liken PAH to cancer. Certainly, without treatment, this disease has a prognosis somewhat worse than metastatic breast cancer (as outlined in a recent MD Anderson Cancer Centre report). What is the current standard of care in Australia for the management of PAH? The notion that only one pathogenic pathway is involved in an individual PAH patient is likely to prove a false expectation. We need to consider blocking at least two or three of the main acknowledged pathways that regulate the pulmonary vascular bed. In Australia, patients generally start on an endothelin antagonist which is probably the most effective oral agent. We tend not to use sildenafil first line: to be effective, sildenafil often requires doseescalation for which we do not have reimbursement. In addition, the antiproliferative properties of endothelin antagonists are important; drugs like sildenafil do not have as effective antiproliferative properties. Once a patient is established on an endothelin antagonist, failure to significantly respond will result in stepwise addition of sildenafil (or new investigational agents) and if additional treatments are required a prostanoid (which may include continuous intravenous epoprostanol) is added. Patients may survive longer with treatments but do patients experience quality survival? Initially patients were prescribed treatments to improve functional capacity but what has now become clear is that patients are living longer. So yes, patients do have greater quantity and quality of survival.