Pathological disease in the lung periphery after acute COVID-19

As we progress through the pandemic phase of COVID-19, the burden of so-called long COVID, a chronic illness with ongoing multidimensional symptomatology and disability after SARS-CoV-2 infection, has become evident.¹ Current prevalence estimates for long COVID suggest that 1–2 million people in the UK are affected.2, 3

Data acquired from people with long COVID indicate that respiratory symptoms are among the most prevalent. For example, the UK Office for National Statistics has highlighted that breathlessness is the second most common symptom after tiredness in people at least 12 weeks after infection.² A systematic review and meta-analysis of persistent or long-term symptoms following acute COVID-19 showed that breathlessness was present in 24% of patients and cough was present in 19%.⁴ The REACT study has reported two long COVID symptom clusters, one of which was dominated by respiratory symptoms.³ The burden of both respiratory and non-respiratory symptoms appears to be even greater in patients who were hospitalised with acute COVID-19 than in those who were not, with failure to fully recover being reported in 30–50% of people who were hospitalised.5, 6

These observations point to a high burden of respiratory symptomatology in patients with long COVID. Studies that have evaluated lung function after COVID-19 are limited to patients who were hospitalised. However, follow-up data are available in approximately 1000 individuals for 2–7 months after infection,5, 6, 7, 8, 9 and in 83 individuals with 12 months' follow-up.⁹ The group mean data from these studies have consistently shown a normal ratio of FEV₁ to forced vital capacity (FVC), with a normal forced expiratory flow at 25–75% where reported. The largest of these studies found that 10% of the participants had evidence of airflow obstruction, but this finding was in line with the proportion that had pre-existing obstructive lung disease.⁵ By contrast, most but not all of these studies reported abnormal lung diffusion in approximately one-third of patients.

In a prospective, longitudinal, phenotyping study that followed the outcomes of people who had been hospitalised with acute COVID-19 infection over a 12-month period, Wu and colleagues⁹ used a combination of detailed lung function measurements, CT lung imaging, and clinical characterisation to report the longer-term sequelae of COVID-19. The study excluded patients who had been ventilated for COVID-19 or who had pre-existing respiratory disease. The results of the study need to be interpreted in the context of these exclusion criteria, as they are likely to underestimate the ongoing burden of disease in less selective cohorts. Only 5% of participants reported any breathlessness at month 12, according to the modified Medical Research Council dyspnoea scale. However, despite this improvement in the majority of patients and a low burden of respiratory symptomatology, a striking proportion of participants had abnormal diffusing capacity of the lungs for carbon monoxide (DLCO) at month 12 (5% had a DLCO of <60% predicted and 33% had <80% predicted), indicative of disease in the lung periphery. CT imaging did not identify any cases of progressive lung fibrosis, and only one participant had developed bronchiectasis.

How can we interpret the findings from these studies? First, there is little evidence to show a meaningful persistent impairment in the large or small conducting airways, although longer-term studies that incorporate imaging in a more mixed population, including patients who were ventilated, are required. Second, there might be pulmonary capillary disease alone (particularly given the common vascular effects of COVID-19 infection), in which case DLCO might decrease, consistent with the abnormal DLCO levels that have been identified across several studies. This fall in DLCO might be associated with parenchymal destruction, in which case the total lung capacity, FVC, and residual volume would also decrease. However, without more detailed reporting of the carbon monoxide transfer coefficient and alveolar volume—the two components that define the single-breath carbon monoxide diffusion test—it is difficult to dissect fully the pathological abnormality in the lung periphery in long COVID. An exploratory hyperpolarised ¹²⁹Xenon MRI study in patients approximately 6 months after acute COVID-19 infection showed striking reductions in the ratio of ¹²⁹Xe in red blood cells to tissue plasma, despite near-normal CT imaging and preserved lung function.¹⁰ These observations further support the notion that damage to the alveolar–capillary interface might be a hallmark of the longer-term pathogenesis of COVID-19 lung disease.

How can we proceed to resolve pathological disease from symptoms alone following COVID-19 infection? Some health-care economies have established effective long COVID surveillance clinics. Given the apparent discordance between respiratory symptomatology and peripheral lung disease observed, it might be prudent to ensure that all patients presenting to these clinical services are offered detailed pulmonary function testing, including diffusion measurements. For those patients who are triage-positive in these tests, more detailed imaging and physiological testing could be done, such as inspiratory and expiratory CT scanning with quantitative radiological analysis, cardiopulmonary exercise testing, and ¹²⁹Xe MRI, to identify abnormal physiological host response or pulmonary vascular gas transport abnormalities due to COVID-19 pulmonary vasculopathy. These tests, coupled with deeper phenotyping, such as multi-omics using patient-derived samples, might provide insights into biological mechanisms for the long-term impact of COVID-19 on lung function and identify specific populations that warrant relevant therapeutic interventions.

Until that time, the studies exploring lung function after COVID-19 infection provide important clues—a whisper—from the quiet zone of the lung and indicate that a more precise understanding of the pathogenesis of organic lung disease after COVID-19 infection, focusing on the lung periphery, is warranted.

© 2021 Lisbeth Hjort/Science Photo Library

SS has engaged in consultancies or received speaker fees from Boehringer Ingelheim, Chiesi, Novartis, GlaxoSmithKline, AstraZeneca, ERT Medical, Owlstone Medical, CSL Behring, Mundipharma, and Knopp Biotech, outside of the submitted work. CEB has received consultancy fees or grants paid to his institution from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Genentech, Roche, Sanofi, Regeneron, TEVA, Merck Sharp & Dohme, Mologic, CSL Behring, Gossamer, and 4DPharma, outside of the submitted work.