Unexplained breathlessness: Integrating pathophysiological insights with clinical evaluation

Abstract

Unexplained breathlessness is a challenging symptom encountered across diverse medical conditions. This review will briefly overview the interplay between central neural mechanisms and peripheral receptor activity leading to symptom perception. A holistic and multidisciplinary approach to unexplained breathlessness is crucial to assess and optimise known comorbidities, as well as investigate potential less common conditions associated with dyspnoea. Specific advanced testing modalities will be briefly discussed in the context of breathing pattern disorders, laryngeal hyperreactivity, disorders of the pulmonary vasculature, autonomic dysfunction and cardiovascular diseases.

Keywords: Cardiopulmonary exercise testing; Complex breathlessness; Exertional dyspnoea; Unexplained breathlessness.

Graphical abstract

Fig. 1

Schematic representation of the central and peripheral mechanisms involved in the perception of breathlessness. Respiratory muscle activity stems from the integration of motor commands from the medulla and motor cortex at the spinal motor neuron level. This activation of respiratory effectors generates afferent feedback that is relayed back to both the motor command centres and the somatosensory cortex. Here, a comparison occurs between the corollary discharge – a copy of the motor command sent to the somatosensory cortex – and the actual afferent feedback, potentially leading to a sensory mismatch (also referred to as ‘neuromechanical dissociation’). Dyspnoea arises when the limbic cortex attributes negative emotions to this mismatch, adding an affective dimension to the experience. Dotted lines indicate the corollary discharge.

Fig. 2

Overview of cardiopulmonary exercise testing. The figure explains a few key CPET parameters among the many physiological measures it provides. VO_2, oxygen uptake; HR, heart rate; SV, stroke volume; O₂, oxygen; V_T, tidal volume; B_f, breathing frequency; BPD, breathing pattern disorders; IC, inspiratory capacity.