Breathing difficulties after covid-19: a guide for primary care

Dear Editor

Breathing difficulties in the post-acute phase of COVID-19 are complex and need to be understood from an interdisciplinary viewpoint. As yet, there are no existing agreed guidelines for imaging-based investigation of these debilitating symptoms.

In the acute phase of COVID-19, radiological studies indicate a pro-thrombotic pulmonary vasculopathy with limited macroscopic airways inflammation.[1-4] Pulmonary vascular congestion is a dominant histological finding post-mortem and is present in areas which are macroscopically normal on pre-mortem computed tomography (CT).[5-7] The underlying pathology of acute COVID-19 lung disease is widely understood to be due to endothelial dysfunction and immunothrombosis (inflammatory-mediated microscopic clotting in situ).[8-9] Dual Energy CT (DECT) demonstrates perfusion defects analogous to pulmonary thromboembolic disease as a universal finding in acute COVID-19 patients hospitalised with respiratory symptoms. These perfusion defects indicate microangiopathic processes driven by immunothrombosis.[10-11] Conversely, the finding of macroscopic airways inflammation is incompatible with the diagnosis of acute COVID-19[2]. Thus, the acute phase lung disease forms part of a systemic vascular disease, rather than a conventional respiratory pneumonia which may or may not be complicated by vasculopathic entities.

In some patients who are severely affected in the acute phase there is a late-stage lung fibrosis[12,13] It is important to appreciate that this fibrosis is a different entity from the pathophysiology of long COVID and does not account for persistent breathing difficulties in those not hospitalised. In patients experiencing respiratory symptoms at three months following acute infection, DECT demonstrates persistent visible pulmonary arterial filling defects (indicating macrothrombosis) in 5%, and persistent perfusion defects (indicating microthrombotic processes) in 65%.[14] This phenomenon does not depend on the presence of lung fibrosis.

Xenon MRI is a research tool which elucidates pathological processes in the lungs of those with long COVID. These studies show failure of gas transfer. Persistent pathological processes in the pulmonary vascular compartment are implicated, rather than failure of the respiratory airways compartment of the gas exchange unit.[15-18]

The pathophysiology of long COVID is complex and is thought to incorporate dysbiosis, endothelial disease, autoimmunity, dysautonomia, the potential for viral persistence, and microclots (circulating microscopic fibrinoid clots resistant to fibrinolysis).[19] Videomicroscopy demonstrates capillary rarefaction (loss of capillary density) in the oral cavity in the setting of long COVID. This phenomenon implicates inadequate response to metabolic demand in peripheral tissues. It is independent of disease severity in the acute phase and there is concern that it could be irreversible.[20]

In use of the term ‘breathing pattern disorder’ it is important that clinicians treating long COVID patients are aware that symptoms could indicate underlying microvascular lung pathology which is occult to conventional imaging. Although supportive measures and respiratory physiotherapy may have a role, it is important not to ascribe breathing difficulties to ‘de-conditioning’ without further investigation.

Currently no agreed imaging guidance exists for investigating respiratory symptoms in the setting of long COVID. The article rightly suggests referral for a chest radiograph to look for other causes of symptoms. However, the absence of pulmonary fibrosis, macroscopic thromboembolic disease, or other lung parenchymal abnormality should not be taken as an indicator that there is no underlying pathology. Rather, it should be understood that plain radiographs are not sensitive for detection of the underlying pathology of long COVID, and neither is CT pulmonary angiography, the conventional imaging modality for detection of thrombotic disease.[14,21] Imaging modalities which are capable of demonstrating perfusion defects are proposed as the best investigations in the context of respiratory symptoms of long COVID. These include DECT and nuclear medicine VQ scans.[21]

Further collaborative development of clinical pathways to optimise investigation and management of long COVID patients is required.

REFERENCES
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[12] Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, et al. Six-Month Follow-up Chest CT findings after Severe COVID-19 Pneumonia. Radiology 2021;299:E177–86. https://doi.org/10.1148/RADIOL.2021203153

[13] Solomon JJ, Heyman B, Ko JP, Condos R, Lynch DA. CT of post-acute lung complications of COVID-19. Radiology 2021;301:E383–95. https://doi.org/10.1148/RADIOL.2021211396

[14] Remy-Jardin M, Duthoit L, Perez T, Felloni P, Faivre JB, Fry S, et al. Assessment of pulmonary arterial circulation 3 months after hospitalization for SARS-CoV-2 pneumonia: Dual-energy CT (DECT) angiographic study in 55 patients. EClinicalMedicine 2021;34:100778. https://doi.org/10.1016/J.ECLINM.2021.100778

[15] Saunders LC, Collier GJ, Chan H-F, Hughes PJC, Smith LJ, Watson J, et al. Longitudinal Lung Function Assessment of Patients Hospitalized With COVID-19 Using 1H and 129Xe Lung MRI. Chest 2023;0. https://doi.org/10.1016/J.CHEST.2023.03.024

[16] Li H, Zhao X, Wang Y, Lou X, Chen S, Deng H, et al. Damaged lung gas exchange function of discharged COVID-19 patients detected by hyperpolarized 129Xe MRI. Sci Adv 2021;7. https://doi.org/10.1126/SCIADV.ABC8180

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[19] Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 2023;21:133. https://doi.org/10.1038/S41579-022-00846-2.

[20] Osiaevi L, Schutze A, Evers G, Harmening K, Vink H, Kumpers P et al. Persistent capillary rarefication in long COVID syndrome. Angiogenesis; 2023;26(1):53-61. https://doi.org/10.1007/s10456-022-09850-9

[21] Dhawan RT, Gopalan D, Howard L, Vicente A, Park M, Manalan K, et al. Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19. Lancet Respir Med 2021;9:107–16. https://doi.org/10.1016/S2213-2600(20)30407-0