We analyzed the impact of COVID-19 pneumonia on follow-up pulmonary function tests. We identified factors during hospitalization that were related to abnormalities in lung diffusion capacity at the time of follow-up. The fact that there was no evidence of restrictive lung disease or anemia in our cohort suggests that the underlying pathophysiological mechanism relates to abnormal pulmonary vascular and thrombotic issues instead of persistence of pulmonary parenchymal abnormalities. Several previously published reports indicate that the majority of ground glass opacities clear in a short period of time after COVID 19 pneumonia. [17, 18] A case series of 149 patients [19] showed near complete radiological resolution on CT 3 weeks after discharge but there was faster clearing of parenchymal abnormalities in younger patients.
Several previous studies of patients that had COVID-19 pneumonia have shown diffusion capacity to be the most common pulmonary function test abnormality at follow-up. A prospective longitudinal cohort from the Netherlands found decreased diffusion to be the most frequent abnormality in 101 patients.[11] Similar findings were seen in two retrospective series from China. [7, 12] In a smaller series from Germany with 33 patients, decreased diffusing capacity was seen in 77% of patients and it was the only significant abnormality on complete pulmonary function tests.[20] Likewise, in 110 patients discharged after COVID-19 pneumonia, decreased diffusion was seen in 47.2% of cases, being more common than obstruction or restriction.[8] More recently, a systematic review and meta-analysis concluded after COVID-19 pneumonia the most important of the pulmonary function tests affected was diffusing capacity of carbon monoxide.[21]
Although we did not find a difference between groups in D-dimer levels, it has been reported. The relation between D-dimer elevation during hospitalization and decreased diffusing capacity in follow-up has been previously described by Zhao et al. [12] in a series with 55 patients. In the multivariable logistic regression model it was found that higher level of D-dimer at admission were associated with follow up DLCO < 80% predicted (p = 0.031, OR 1.066, 95% CI 1.006 to 1.129). Another study from Spain [22] with a larger cohort also found a relationship between maximum D-dimer levels and lower diffusing capacity in subsequent pulmonary function testing. Our report used peak D-dimer during hospitalization instead of D-dimer at admission. D-dimer levels during hospitalization have shown to have a relationship with mortality, thromboembolic events and need for invasive mechanical ventilation. [23]
Pulmonary vascular abnormalities in COVID 19 pneumonia have been widely reported. Using CT pulmonary angiography and dual energy CT, a retrospective series of 39 mechanically ventilated patients with COVID 19 pneumonia [24] found dilated peripheral vessels (vascular tree-in-bud pattern) and arterial filling defects in the majority of cases. Very similar findings were seen in another retrospective study of 85 patients [25]; their pulmonary dual energy CT angiography revealed a significant number of pulmonary ischemic areas even in the absence of visible pulmonary arterial thrombosis, raising the possibility of micro thrombosis associated with COVID-19 pneumonia.
Other chronic pulmonary conditions have also shown pulmonary vascular remodeling; using CT chest for reconstructions of the pulmonary vasculature in patients with chronic thromboembolic pulmonary hypertension (CTEPH), compared to healthy controls there was loss of the distal vessels, dilation of the proximal vessels and increased vascular tortuosity. [26] In a study of smokers,[27] loss of the small blood vessels (< 5 mm2) was found. The magnitude of the changes was correlated to the clinical severity of their lung disease.
Regarding the assessment of small pulmonary blood vessels in our cohort, the paper by Lins et al. [13] has already shown that patients with COVID-19 pneumonia compared to healthy individuals seem to have redistribution in the blood volume with decrease in blood vessels with an area less than 5mm² and an increase in the blood vessels with an area of 5 to 10mm² and more than 10 mm². This has been commonly interpreted as evidence of elastic pulmonary arterial dilation proximal to areas of increased pulmonary vascular resistance downstream; the dilation of vessels more proximal than those smaller than 5 mm2 leads to an increase in BV5_10 and 10 and a reduction in BV5. This may be suggestive of persistent dysregulation of pulmonary vascular tone which could contribute to reduced diffusing capacity.
Our data show that COVID-19 pneumonia patients with pulmonary vascular abnormalities have an associated low diffusing capacity in follow-up pulmonary function tests. This has biologic plausibility, considering the profound pathologic changes seen in lungs obtained during autopsy with patients who died from COVID-19 pneumonia. [3] Changes include severe endothelial injury with disruption of cell membranes, capillary microthrombi and new vessel growth with widespread angiogenesis. Additionally, in a recent study, [28] 83% of patients with severe COVID-19 pneumonia have evidence of intrapulmonary right to left shunt, which is more evidence of profound vascular anomalies. Our findings support that the presence of pulmonary vascular remodeling in COVID-19 pneumonia patients can predict future isolated impairment in diffusing capacity.
Our study has several limitations. Firstly, our cohort is small and our data were retrospectively collected. Secondly, due to several logistic reasons we did not see all of our patients at the same time after discharge in a protocol driven fashion. Ideally, the pulmonary function tests would have been done at the same time after diagnosis of COVID-19 pneumonia to avoid confounding by the natural history and progression of COVID-19 related pulmonary disease. Thirdly, the elevation of serum D-dimer levels during hospital admission could have impacted treatment decisions that might have influenced subsequent pulmonary function testing and diffusing capacity. Finally, many of the patients hospitalized at our institution were lost to follow-up for many reasons (unable to contact, discharge to long-term care facility after hospitalization, death, etc.). This may have skewed our data towards less sick patients.