This study characterized a subset of the COVID-19 CORE clinic patients. The major findings are: i) dyspnea, fatigue, decreased exercise tolerance, brain fog, and shortness of breath were the most common symptoms, ii) some patients have abnormal physical, emotional, and cognitive scores but most are able to live and function independently, iii) some variables of the 6MWT, LUS, and diaphragm excursion are abnormal in the hospitalized cohort, suggestive of interstitial lung disease, iv) pulmonary function tests suggest moderately restrictive pulmonary function in the hospitalized cohort but no obstructive pulmonary function nor air trapping in the lung, v) newly detected major neurological events, microvascular disease, atrophy, and WM changes are rare, and vi) many patients have persistent lung opacity and fibrosis-like findings post-COVID-19.
Symptom, physical, emotional, and cognitive assessments
The high incidence of dyspnea, fatigue, brain fog, decreased exercise tolerance, and shortness of breath are consistent with the literature. Goertz et al. found that fatigue, dyspnea, headache, and chest tightness were the four most common persistent symptoms across both hospitalized and non-hospitalized COVID-19 patients 3-months after infection 33. Huang et al reported that fatigue or muscle weakness was by far the most common symptom hospitalized COVID-19 patients at 6-months followed up34. Carfi et al. found fatigue, dyspnea, and joint pains to be the three most prevalent symptoms in COVID survivors about 2 months after their COVID-19 hospitalization 35.
Collectively, ADL, IADL, and frailty marker scores indicate the CORE patients have mild dependency and prefrailty. Although CORE patients showed signs of anxiety, depression, and PTSD, they were below the clinical cutoff in both hospitalized and non-hospitalized patients. Other studies reported clinically significant neurological and psychiatric symptoms after COVID-19 diagnosis36.
Surprisingly, there were few differences in symptom, physical, emotional, and cognitive scores between hospitalized and non-hospitalized cohort. A likely explanation is that non-hospitalized COVID-19 patients who visited our CORE clinics likely had more symptomatic COVID-19 disease. Previously studies have reported individuals with mild symptoms from SARS-CoV-2 infection (i.e., not requiring hospitalization) may also be susceptible to neuro-PASC12,13.
Pulmonary assessments
For most pulmonary measures, only the hospitalized cohort exhibited abnormalities. Both 6MWT distance and maximum heart rates were below normal (compared to some normative means) because patients as a cohort were not able to accomplish the task. 6MWT and SpO2 saturation were clearly abnormal in the hospitalized cohort. Note that the normative data used for reference were from a very different population that were not matched (i.e., for age or sex, etc) and thus comparisons need to be interpreted with caution.
LUS has been previously used to measure degree of loss of aeration in patients with acute respiratory distress syndrome, with higher scores indicating more loss of normal lung aeration. B-lines in lung ultrasound denote artifacts reflecting a widening of the interlobular septa of the secondary pulmonary lobule. As a result, this finding is non-specific, and in acute respiratory failure may represent cardiogenic or non-cardiogenic pulmonary edema as in ARDS, or other diagnoses 37. In the post-COVID-19 population however, high LUS likely denote presence of interstitial lung disease and lung injury following severe viral pneumonia. The abnormalities in spirometry measurements are suggestive of residual lung disease likely from covid pneumonia. Our spirometry analysis did not account for lung volume differences among patients thus such comparisons need to be interpreted with caution.
A combination of moderately reduced FVC%, FEV1%, RV/TLC ratio and DLCO% were abnormal in the hospitalized cohort, suggesting of restrictive pulmonary function and air-trapping. FEV1/FVC in the hospitalized cohort was however normal, suggesting there was no significant obstructive pulmonary function. A normal FEV1/FVC ratio with a decreased FVC indicates a restrictive lung condition, which include pulmonary fibrosis and infections like pneumonia. A decreased FEV1/FVC ratio indicates an obstructive condition, such as asthma or COPD. In contrast, all these PFT variables were normal in the non-hospitalized cohort.
Imaging findings
Although the sample size for brain imaging is small and both brain MRI and CT were included (which provide different sensitivity to detection of abnormalities), the main findings will likely hold, namely, that newly detected major neurological events post-COVID-19 are rare, and newly detected MVD, atrophy, and WM changes are also rare 5 months post -COVID-19 in our cohort. We thus concluded that there is no evidence of widespread changes on routine clinical brain imaging in our CORE patients 5-month post-COVID-19. However, it is possible that subtle brain changes existed, but were not detectable by routine clinical imaging. Imaging studies using more advanced imaging methods (such as diffusion tensor imaging, quantitative susceptibility mapping, and functional MRI) are warranted.
That said, it is surprising that given the broad spectrum of neuro-PASC symptoms reported in this cohort, there were comparatively few observable radiological abnormalities post-COVID-19. It is possible that these symptoms and neurological abnormalities have not yet manifested into structural changes in the brain on routine clinical imaging methods, and thus longer follow up and more sophisticated imaging tools are necessary.
A few studies have reported brain imaging findings in post COVID-19 patients. A cohort study found a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and para-hippocampal gyrus, greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex and a greater reduction in global brain size in the COVID-19 cases compared to negative controls 38. Abnormalities and cerebral microstructural changes in the brain of COVID-19 survivors both with and without neurological manifestations were noted 39,40, and persistent WM changes and ischemic stroke associated with COVID-1941,42. Note that many published studies to date were case reports or did not have pre-COVID-19 imaging data or controls (including the current study), which makes it difficult to definitively discern whether imaging abnormalities were pre-existing or a consequence of COVID-19 disease. Thus, there is likely reporting bias of positive clinical imaging findings associated with COVID-19. Brain imaging studies with proper controls with correlation of neurological function at longer follow-up intervals are needed.
In contrast to brain imaging findings, there is clear anatomical abnormalities in the lung 5 months postCOVID-19. It is concerning that lung opacity in many patients has not completely resolved and that many patients developed pulmonary fibrosis-like changes 5 months after COVID-19. Pre-COVID-19 abnormalities were very rare and thus essentially all new lung findings were due to COVID-19. Hospitalized patients had more opacity and fibrosis-like changes post-COVID-19, consistent with disease severity. The incidence of fibrosis-like changes is likely underestimated in our study because chest radiograph was included which has lower sensitivity for fibrosis detection compared to CT.
A few studies have previously reported persistent fibrosis-like lung changes post-COVID-19. CT abnormalities were common at 3 months after COVID-19 but with signs of fibrosis in a minority. More severe acute disease was linked with CT abnormalities at 3 months 43. One study reported that although COVID-19 survivors showed continuous improvement on chest CT, residual lesions could still be observed and correlated with lung volume parameters one year post-COVID-19 and the risk of developing residual CT opacities increases with age 44. Another study found a significant percentage of individuals develop pulmonary sequelae after COVID-19 pneumonia, regardless of severity of the acute process 45. Six-month follow-up CT showed fibrotic-like changes in the lung in more than one-third of patients who survived severe COVID-19 pneumonia. These changes were associated with an older age, acute respiratory distress syndrome, longer hospital stays, tachycardia, noninvasive mechanical ventilation, and higher initial chest CT score 46. Given the numerous reports of persistent post-COVID-19 pulmonary sequela in many COVID-19 patients, longitudinal monitoring by chest imaging and pulmonary function in at-risk patients is warranted. Moreover, SARS-CoV-2 infection could also worsen existing pulmonary diseases. Many COVID-19 survivors are already being treated by pulmonary medications and pulmonary rehabilitation for pulmonary sequela.
Limitations
This study has several limitations. Our findings were limited to COVID-19 survivors who came to our CORE clinics and who were more likely to have more severe COVID-19 symptoms, and thus our cohort was not representative of the general population. It was not possible to definitively distinguish abnormalities that were due to COVID-19, pre-existing or worsened by COVID-19 disease although attempts were made to evaluate patients’ pre pandemic data. Sample sizes of imaging data were small and consisted of a mixture of imaging modalities with different sensitivity to pathology, and thus results must be interpreted with caution. The small sample size also precluded quantitative statistical parametric analysis of imaging data. Large multicenter longitudinal imaging studies with proper controls are needed. We hope to be able to report longer follow-up findings on this cohort in the future.