“Physicians have to be satisfied they have an adequate explanation. “If we make an initial diagnosis but the treatment is ineffective, then we need to keep looking.” – Associate Professor Eugene Kotlyar, St Vincent’s Hospital, Sydney.
Uncovering the many hidden causes of chronic breathlessness in an otherwise healthy patient can be a minefield for physicians – the non-specific symptom 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.
Ruling out is as important as ruling in
Speaking to the limbic about the challenges associated with diagnosing and treating the debilitating disease, cardiologist Associate Professor Eugene Kotlyar, from the pulmonary hypertension service at St Vincent’s Hospital in Sydney, says that any patient with breathlessness that is unexplained should be followed until the cause becomes clear.
“Physicians have to be satisfied they have an adequate explanation,” he says. “If we make an initial diagnosis but the treatment is ineffective, then we need to keep looking.”
Pulmonary arterial hypertension (PAH) is rare but needs to be considered after other causes have been considered and excluded, Professor Kotlyar told the limbic.
“PAH is a potentially lethal condition, but if it is detected and treated early then it can be manageable and controllable” he says.
According to Dr Kotlyar, very early diagnosis is so important to being able to improve patient outcomes that it should always be considered and ruled out in patients whose breathlessness doesn’t appear to have another cause.
“In my experience the earlier you diagnose and start treatment as aggressively as possible the best chance we’ve got to slow down the progression of this condition – to the point where a patient can live a relatively normal life.”
When Dr Kotlyar began specialising in pulmonary hypertension some 20 years ago outcomes for patients diagnosed with PAH – defined by an elevated resting mean pulmonary artery pressure of ≥25mmHg and pulmonary artery wedge pressure ≥15mmHg – were vastly different than the story he tells today.
“There’s been a dramatic change in survival especially over the last decade. If we talk about idiopathic PAH for example it used to be that a third of patients died within a year of being diagnosed and two thirds died at five years.
Now the pulmonary hypertension registries both in Australia and overseas are seeing an improvement at 90% survival at one year and around 77% survival at five years with the availability of advanced PAH-specific therapies.”
But the relative rarity of PAH – a recent Western Australian population-based study estimates it affects around 150 people per one million1 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.
A silent disease
According to Dr Kotlyar in its early stages PAH can remain relatively silent for years and symptoms are not likely to cause discernible problems.
He said initial symptoms typically include shortness of breath, fatigue, weakness, angina and syncope. Less commonly, patients may also describe dry cough and exercise-induced nausea and vomiting.
Meanwhile, abdominal distension and ankle oedema will develop with progressing right ventricular failure.
“The basic tests – ECG, chest x-ray, spirometry – can sometimes come up with nothing abnormal in the very early stages of PAH. If that’s the case you really need to keep looking; run more in depth tests, do an echocardiogram, get a proBNP level and lung function test or a CT scan of the chest. You must keep looking further until you can find an explanation for a patient’s breathlessness.”
And if you can’t find an explanation, consult with other specialists in the field, he advises.
“I would refer a patient to an Expert Centre or talk to other colleagues whenever you can’t get to the bottom of a patient’s breathlessness.”
An epidemiological shift towards the elderly
Also speaking to the limbic Dr Edmund Lau, a respiratory physician and PAH specialist at the department of respiratory medicine at the Royal Prince Alfred hospital, Sydney, says that local registry 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.”
According to Dr Lau Australian registry data along with similar findings 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 and drug-induced PAH, of whom 220 were diagnosed since 2012.2 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.
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.
“Its 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 new 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 approach3
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 import 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.3
Lung function tests could also show a disproportionate reduction in carbon monoxide diffusion in the lung with a mild-to-moderate restrictive lung defect.
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 and ≥30 mmHg with exercise, Dr Lau added.
Meanwhile Dr Kotlyar warned older males might be at risk more than other populations of falling through the cracks when it comes to an early PAH diagnosis.
“There is some misconception that PAH is usually a female disease but there’s a bimodal age distribution – in fact males and female are equally affected in later years as opposed to younger years where there is a more female dominance.
Older people often say, I thought I was breathless because I’m getting old and unfit but you can’t assume that – you need to run the tests and make sure it’s not anything else.
- 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.