“If you can’t find a good explanation for a patient presenting with breathlessness, keep in mind the possibility of pulmonary arterial hypertension and test for it early – the availability of new therapies means that early diagnosis and referral of patients with this rare but increasingly prevalent disorder can make a substantial difference to patient outcomes.” Dr Edmund Lau, respiratory physician and PAH specialist, department of respiratory medicine at the Royal Prince Alfred hospital, Sydney.
Uncovering the many hidden causes of chronic breathlessness in an otherwise healthy patient can be a minefield for physicians – the non-specific symptoms associated with a variety of common cardiac and pulmonary conditions will see patients put through a barrage of clinical, laboratory, and imaging tests in an effort to diagnose the underlying disease.
Most cases of chronic breathlessness will eventually be attributed to conditions such as asthma, congestive heart failure, COPD, pneumonia, cardiac ischaemia, interstitial lung disease and even some psychogenic conditions.
But for some patients, experts warn that breathlessness may be a very early signal of less common cardiorespiratory conditions – one of the most serious of which is pulmonary arterial hypertension (PAH).
Ruling out is as important as ruling in
Speaking to the limbic about the challenges associated with diagnosing and treating the debilitating disease, PAH specialist Dr Lau said while very few patients with dyspnoea consulting a respiratory physician or referred to a PAH Expert Centre will be diagnosed with the disease – defined by an elevated resting mean pulmonary artery pressure of ≥25 mmHg – very early diagnosis is important to being able to improve patient outcomes and should always be considered and ruled out in patients whose breathlessness doesn’t appear to have another cause
“If you can’t find a good explanation for a patient presenting with breathlessness, keep in mind the possibility of pulmonary arterial hypertension and test for it early – the availability of new therapies means that early diagnosis and referral of patients with this rare but increasingly prevalent disorder can make a substantial difference to patient outcomes.”
When Dr Lau began specialising in pulmonary hypertension over a decade ago it was an exciting time for researchers investigating the group of rare and deadly conditions; promising new treatments were becoming more widely available in Australia and all of a sudden cardiologists and respiratory physicians, who once had very few drug therapies to turn to, could now make real headway improving not just their patients’ quality of life but also significantly improving survival outcomes.
“If you look at the traditional data from the 1980s investigating the natural history of people with PAH on average the median survival was about two-and-a-half to three years –it was a very deadly condition that was picked up mostly in young females aged around 30-40 and people had to rely on getting a lung transplant or, inevitably, they would succumb to the illness.”
Making progress
Some two decades on and the development of three classes of PAH specific therapies have seen evolving evidence for improved survival gathered from global registries and data from contemporary studies indicating an overall 43%1 reduction of mortality in actively treated patients compared to no treatment
But the relative rarity of PAH – a recent Western Australian population-based study estimates it affects around 150 people per one million2 in Australia – and the fact that the early stage of the disease is plagued by non specific symptoms often thwarts a prompt diagnosis or referral to specialist centres.
“We have a much better opportunity to intervene and improve long term patient outcomes the earlier the condition is diagnosed,” noted Dr Lau explaining the World Health Organization grading system used to understand the extent to which PAH symptoms are affecting lifestyle and well-being: Class I describes people with PAH who experience no limitation in daily function, progressing to class IV which describes patients who are unable to perform any physical activity and have symptoms at rest, indicating more severe PAH.
“We know from registry data that if patients are picked up in functional class II and they do not have evidence of right heart failure for instance then they do a whole lot better than a patient who is diagnosed with PAH in functional class IV.”
A silent disease
But the problem with PAH is that in its early stages it can remain relatively silent for quite a long time.
The only symptoms that patients might get are fatigue, lethargy and feeling just a little more breathless compared to what they have been,” noted Dr Lau adding that a clinical examination at this stage can appear relatively normal.
“In the case of idiopathic PAH where there is no underlying predisposition, you can look at a patient with unexplained dyspnoea and they might look completely normal in front of you – you won’t hear noises in the chest and the patient may not have any symptoms of heart failure at this point but they actually have early stages of PAH”.
Dr Lau says that data suggests many Australian patients with PAH experience a delay of 18-24 months or even longer from symptom onset to diagnosis and treatment.
“Unfortunately that is not something that has changed over the past decade,” he told the limbic.
He says unless PAH is actively investigated, many patients will spend crucial months taking medications for other more common conditions while the disease progressively leads to right ventricular failure.
“We need to be aware that if standard treatment for asthma for example does not improve symptoms and you still have no cause then you need to think about PAH. Do the appropriate investigations that might give you a hint as to whether a patient may have PAH or refer them to a specialist centre early for a definitive opinion rather than waiting the 12 or 24 months for the more obvious symptoms of heart failure to manifest.”
An epidemiological shift towards the elderly
According to Dr Lau the Australian registry data along with similar finding in registries overseas indicate a significant shift in the epidemiology of the disease over the past two decades.
A recent analysis of the 3,240 patients enrolled in the registry included 920 with a primary diagnosis of idiopathic, heritable or drug-induced PAH, of whom 220 were diagnosed since 2012.3 The mean age at diagnosis was 57 years and 45% were older than 65. Women outnumbered men by a ratio of 2.2 to one.
“When you look at data from the 1980s that describe someone with idiopathic PAH its normally a female in their 30s or 40s. Now we’re actually seeing a lot more elderly people that have PAH. Right now from our current Australian database the average age is approximately 50-55 years so that’s been a really big shift towards a lot more elderly people being diagnosed with the condition compared to 20 or 30 years ago.”
He suggested that might be a result of improved case recognition in the elderly as more effective treatments have become available.
“Because in the past there was no treatment for this condition many of us did not investigate further especially if the patient was a little more elderly. Now we can offer treatment, if it’s appropriate, to patients in their 70s and even 80s so I think that has led to a lot more case recognition among the elderly population.”
Despite this, Dr Lau says one of the biggest barriers to combatting the disease continues to be a critical delay in diagnosis – a factor he acknowledges is not easy to overcome considering the hallmark of early stage PAH is breathlessness.
“It’s very hard to provide hard and fast rules as to when you should investigate breathlessness right to the end because there are limited resources and you don’t want to put patients through every single test under the sun – but, if the symptoms are progressive, if someone is getting worse with time or if you just have no explanation for the patient’s symptoms then those are warning signs and there needs to be a high clinical index of suspicion for less common conditions,” he told the limbic.
When to have a high index of suspicion
According to Dr Lau a significant change in a patient’s exercise capacity should be a red flag suggesting a high index of suspicion for PAH.
“A lot of people become unfit and a little bit deconditioned but it’s not normal for a 30-40 year old to not be able to walk for example more than 500 metres without losing their breath.”
“If you have for example a young patient who was able to exercise and run five days a week previously and now can’t do that then that’s a big change and that’s a big red flag – that’s not just someone becoming a little less fit. You have to put into context whether the patient should have a reason to feel like this.
“On the other hand if you have a frail 70-80 year old man with a lot of other comorbidities and they feel a bit more breathless then maybe you have enough information there to account for the symptoms … I think it does relate to the clinical acumen to some extent and that’s not something that is easy to put into a formula because each patient is different.”
Dr Lau said other red flags, though subtle and subjective, can help doctors decide whether further investigation of PAH is warranted but he stressed that relying on clinical signs alone is inadequate when it comes to picking up early signs of PAH.
“Combined with dypsnoea and fatigue you may see elevated venous pressure, peripheral oedema, congested liver and you may pick up a loud second component of the second heart sound. As the disease progresses then obviously the patient can develop symptoms of heart failure, they might get angina when they exert themselves or may faint but those are relatively late symptoms.”
PAH needs a team approach
Meanwhile recent guidelines of the diagnosis and treatment of PAH issued jointly by The European Society of Cardiology and European Respiratory Society have emphasised the need for a multidisciplinary approach.4
The guidelines include a comprehensive diagnostic algorithm and explain the recommended investigations while emphasising that PAH should be considered in the differential diagnosis of exertional dyspnoea, syncope, angina and/or progressive limitation of exercise capacity, particularly in patients without apparent risk factors, symptoms or signs of common cardiovascular and respiratory disorders.
Patients with risk factors should attract a higher suspicion of PAH. These include a family history of the disease, or the presence of connective tissue disease, coronary heart disease, HIV infection, portal hypertension, or exposure to drug or toxins known to induce PAH.
In everyday clinical practice, though, awareness of these risk factors may be low. “More often PAH is found unexpectedly on transthoracic echocardiography requested for another indication,” the guidelines state.
A normal ECG and chest X-ray do not necessarily exclude PAH. Comprehensive investigations leading to diagnostic right heart catheterisation can include pulmonary function tests, arterial blood gases, echocardiography, ventilation perfusion scans, CT and pulmonary angiography, cardiac MRI, blood tests and immunology, abdominal ultrasound to check for portal hypertension, and genetic testing.
For Dr Lau, the single most important screen to glean whether a patient has PAH is echocardiogram but he argues that comes with a caveat.
“The person who is doing the echo has to be looking out very specifically for signs that may indicate PAH. Sometimes they can be quite subtle and often missed – in a lot of cases it’s not until you have a diagnosis and look back to find an echo from six months ago was actually not normal.”
The echocardiogram may show a hypertrophied, dilated or hypokinetic right ventricle, tricuspid regurgitation and elevated pulmonary arterial pressure.4
Lung function tests could also show a disproportionate reduction in carbon monoxide diffusion in the lung with normal volumes or mild restriction.
A diagnosis of PAH would then be confirmed with right heart catheterisation, providing a direct measure of pulmonary pressures which will be ≥25 mmHg at rest, he added.
“All these tests should be done reasonably quickly and patients should be started on treatment if appropriate. We shouldn’t be waiting two to three months to put these patients through a diagnostic channel before they get started on drugs. I think that’s far too long; we don’t want to delay a diagnosis any further because most of these patients have already been delayed before they get to us.”
References
- Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009; 30:394–403.
- Strange G et al. Pulmonary hypertension and breathlessness: is it a combination we can ignore? Intern Med J 2014; 44: 114-2
- Strange G et al. Survival of idiopathic pulmonary arterial hypertension patients in the modern era in Australia and New Zealand. Heart Lung Circ 2017 Sep 20. pii: S1443-9506(17)31394-X.
- Galiè N et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Respir J 2015; 46: 903-75.