Clinical conundrum: Why is this otherwise well patient persistently breathless?

Dr HK Makker, consultant respiratory physician and Dr Charles Latchford, respiratory clinical research fellow, discuss options for a woman complaining of persistent breathlessness 

Introduction
Breathlessness accounts for around 4% of all GP appointments, with approximately one in three of these presentations having a multifactorial aetiology.¹ A recently proposed tool for approaching breathlessness in the community, Breathing SPACE (Smoking, Pulmonary disease, Anxiety/psychosocial factors, Cardiovascular disease, Exercise), prompts clinicians to consider the interactions between multiple possible contributors during the consultation.² We use this framework to consider possible explanations and investigations. 

What explanations might there be for the patient’s symptoms?
In this case, the presence of S (smoking) is going to draw our focus to P (pulmonary disease), given the absence of any other significant factor on preliminary assessment. 

Normal (expiratory) spirometry and chest radiography does not exclude airflow obstruction, so COPD remains at the top of our differential list for someone with a significant smoking history. Although asthma is unlikely, postviral inflammatory airway disease is now a possibility. Some people with long Covid and atypical asthma-like breathlessness have responded to inhaler therapy.³

In addition, up to one in five patients with interstitial lung disease has a normal chest radiograph; the condition carries a 55% misdiagnosis rate. Breathlessness in patients with ILD, particularly with normal chest radiograph and smoking, is often attributed to other respiratory conditions such as asthma, pneumonia and bronchitis. Smoking is an associated risk factor for multiple types including autoimmune pathology.⁴

Post-Covid sequelae of exertional breathlessness with no organic findings on assessment has been a major contributor to the number of patients presenting with unexplained breathlessness in recent years. The physiology behind this is undetermined, although the most convincing theory lies in an often isolated reduced TLCO (transfer factor) and KCO (transfer coefficient) noted on pulmonary function tests. This supports the theory of thrombotic endotheliitis of the pulmonary endothelium as a potential mechanism.⁵

Preliminary investigations are generally more sensitive in diagnosing the more common causes of breathlessness relating to C (cardiovascular disease). A normal BNP correlated to age and sex almost always excludes left ventricular dysfunction, unless the patient is obese, in which case clinical correlation is advised. BNP is less useful in ruling out pulmonary hypertension in view of potential compensation by the right ventricle against high pulmonary artery pressures. In addition, a normal ECG at rest does not exclude orthostatic-related arrhythmias that cause persistent breathlessness. These include postural tachycardia syndrome (PoTS) and inappropriate sinus tachycardia (IST), which commonly feature in patients with dysautonomia caused by infection. 

When considering A (anxiety), in light of normal investigations, breathing pattern disorders (BPD) – with hyperventilation syndrome at the extreme end of this spectrum – are often over-looked. BPDs occur in 8% of the adult population and often accompany respiratory conditions with organic findings.⁶ However, BPD may also be secondary to comorbidities such as psychiatric disorders, spinal misalignment, pain or a postviral dysautonomia. 

More recent studies have highlighted the significant overlap between BPD and inducible laryngeal obstruction, which also often coexists with asthma but may occur in isolation and be aggravated by comorbidities such as nasal obstruction and gastric reflux.⁷

For E (exercise) loss of aerobic capacity (deconditioning) and obesity are undoubtedly contributors to breathlessness, although this should only be a diagnosis of exclusion following specialist input. 

Are there other investigations the GP should consider?
Unexplained breathlessness is not an uncommon problem and can be difficult to resolve in primary care. Patients should be assessed further by one of the medical specialities: respiratory, cardiac or post-Covid. This will typically be in secondary care, although some ICBs have developed diagnostic pathways through community diagnostic centres. However, these pathways have challenges in that chest physicians are still required to oversee specialist investigation interpretation and diagnosis, and involving consultants at the community level has been logistically difficult. 

The sequence of further investigations will depend on the detailed history of the breathlessness, including the nature of the breathing difficulty and course over time. If spirometry is normal in a patient with a significant smoking history, then full pulmonary function tests would be the most sensible next step. These should include bronchodilator reversibility and gas transfers. Fractional exhaled nitric oxide (FeNO) if available can also be helpful in dissociating inducible laryngeal obstruction from asthma, if the onset of breathlessness is trigger-induced. GPs should consider a standard chest and neck CT, which can be diagnostic if upper airway obstruction is suspected.

Given the patient’s age in this case, a transthoracic echocardiogram should also be considered regardless of normal BNP and normal pulmonary functions, to exclude the handful of patients with cardiac disease such as diastolic dysfunction who present with normal preliminary findings despite breathlessness on minimal exertion.⁸ Ambulatory ECG monitoring is also a relatively simple test for GPs to use for patients who exhibit orthostatic or other atypical patterns of symptomology.

If referral is required, should this be to cardiology or respiratory? How can the GP decide?
If there are no cardiac risk factors or other cardiac symptoms, and the initial cardiac investigation are normal, patients with this presentation should almost always be referred primarily to a general respiratory service. Many services now offer clinics tailored to patients with this presentation, and these often involve healthcare teams such as physiotherapists and speech and language therapy to provide a holistic approach. From here, patients are referred to the most appropriate service based on more specialised investigations, such as pulmonary hypertension clinics or ENT services specialising in airway obstruction. 

Exceptions include patients with a clear onset of symptoms following a Covid-19 infection, where more post-Covid services now offer an integrated service in the community to aid rehabilitation, not just in respiratory services but also in other areas such as psychological and vocational to help patients access their work. It is crucial that GPs keep the ‘SPACE’ framework in mind. Interventions such as smoking cessation and social prescribing such as outdoor swimming, yoga and Pilates can be hugely beneficial. 

Dr HK Makker is consultant respiratory physician and Dr Charles Latchford is a respiratory Clinical Research Fellow, both at University College London Hospitals. 

References

1. Frese T et al. Dyspnea as the reason for encounter in general practice. J Clin Med Res 2011;3(5):239-46. Link
2. Hopkinson, N, Baxter, N. & on behalf of the London Respiratory Network. Breathing SPACE—a practical approach to the breathless patient. Prim Care Resp Med 2017;27, 5. Link
3. Kadir M et al. Post-COVID sequelae: from lung disease to long disease. Cureus 2023;15(3):e35668. Link
4. Schoenheit G et al Living with idiopathic pulmonary fibrosis: an in-depth qualitative survey of European patients. Chronic Respiratory Disease 2011;8(4):225. Link
5. Calabretta E et al. COVID-19-induced endotheliitis: emerging evidence and possible therapeutic strategies. B J Haematol 2021;193:1:43-51. Link
6. Thomas M et al. The prevalence of dysfunctional breathing in adults in the community with and without asthma. Prim Care Respir J 2005;14:78-82. Link
7. Ludlow S et al. Multidisciplinary management of inducible laryngeal obstruction and breathing pattern disorder. Breathe 2023;19(3):230088. Link