Pulmonary perfusion and vessels are frequently abnormal in COVID-19 pneumonia and may point to a key role of pulmonary vascular pathology and hypoxemia in COVID-19 infection [7]. Studies have shown associated lung perfusion abnormalities in patients with severe COVID-19 infection presenting with various respiratory symptoms [2, 5,6,7,8]. These perfusion abnormalities may include mosaic perfusion, focal hyperemia in a subset of pulmonary opacities, and focal oligemia associated with a subset of peripheral opacities [7]. We decided to study the incidence of some of these perfusion abnormalities in non-hospitalized patients diagnosed with mild COVID-19 infection.
A few studies have already reported the use of conventional CT or dual energy CT (DECT) pulmonary angiography in studying some of these perfusion abnormalities [2, 5,6,7,8]. Patelli et al. [2], in their study, demonstrated hypo perfusion in 3 patients with dyspnea, more than 1 month after the diagnosis of COVID-19 infection. Pulmonary thromboembolism was excluded in these patients and a suggestion of persistent microvascular defect was thought to be the reason for the hypo perfusion. Lang et al. [5], in their findings, also demonstrated mosaic perfusion pattern in 3 patients without PE. They proposed that there might be possible perfusion shunting due to increased perfusion to regions of inflammation and decreased perfusion to the area of normal lung parenchyma. Another study by Ling et al. [7] demonstrated hypo perfusion in areas with mosaic attenuation in 96% of their study population who had DECT. In our study, we had 17 cases with one or more perfusion defects not due to PE, but associated with mosaic attenuation on the CT images (Fig. 2).
We also identified 10 cases of increased perfusion to areas with associated inflammation and resulting perfusion defects, in areas with normal lung parenchymal (Fig. 3). This pattern is thought to have resulted from a loss of normal physiologic hypoxic vasoconstriction in areas with inflammation, leading to vasodilatation in this area and possible shunting of blood from areas without inflammation [5,6,7,8]. These studies also identified a possible VQ mismatch in these areas of hypoperfusion as a reason for some of the respiratory symptoms in COVID-19 patients. However, our study shows that these defects are matched on the ventilation study (Fig. 4). This pattern may not be specific to COVID-19 patients, as an earlier VQ SPECT/CT study performed in one of the patients in January 2019 showed a similar pattern (Figs. 5 and 6).
As earlier noted, 10 of the 17 cases with perfusion defects and mosaic attenuation not due to PE had associated increased perfusion to areas of inflammation. This most likely leads to possible shunting of blood from areas of the lung without inflammation. The probable cause of the perfusion defects and mosaic attenuation in the remaining 7 cases is uncertain. We hypothesize that this could either be due to microvascular thrombosis, small airway disease, persistent defect after resolution of a previous shunt, or a rare case of PE with a matching ventilation study.
During the early parts of the COVID-19 pandemic, we omitted the ventilation part of the study, thereby minimizing the possibility of the spread of infection. However, we erroneously attributed some of these perfusion defects to PE, as the corresponding CT images did not show obvious parenchymal CT changes. By the time some of our patients had their follow-up study at 3 months, we had resumed the ventilation aspect of the study. These follow-up VQ studies performed 3 months after the initial perfusion only study confirmed that some of the earlier perfusion defects were matched (Figs. 7 and 8). This highlights the importance of the ventilation part of the study in patients with COVID-19 infection.
Pulmonary embolism is a known thrombotic complication that has been associated with COVID-19 infection [14]. Numerous studies have shown the incidence of PE in this condition [4, 14,15,16,17]. However, the category of most of the patients studied has been hospitalized patients with severe disease, with some of them being admitted into intensive care units [4, 14,15,16,17,18,19,20]. Our study population was that of non-hospitalized patients diagnosed with mild disease. There has not been enough data yet looking at the prevalence or incidence of PE in this group. There are, however, some case reports that have reported the occurrence of PE in non-hospitalized patients diagnosed with COVID-19 infection [21,22,23,24]. In our study, there were 20 (35.7%) cases with defects in keeping with PE (Fig. 9). Follow-up studies performed 3 months after initiation of anticoagulation in some of these patients demonstrated defect resolution (Fig. 10). We suspect that the significant number of cases with PE in our cohort was due to some of the peculiar characteristics of our study population. Our study population only included those patients with persistent or new onset respiratory symptoms and raised D-dimer levels. If we were to include all cases with mild disease, and without respiratory symptoms or raised D-dimer levels, we would most likely have a lower percentage with PE.
Of particular interest, we had a patient who had been symptomatic for about 90 days post de-isolation. The VQ SPECT/CT study performed revealed mismatched defects in keeping with PE. This goes to show that it is very possible that some of these patients might not be diagnosed at all or early enough with PE. This puts them at an increased risk of morbidity or mortality from a second embolus, pulmonary hypertension, or right ventricular failure.
It is known that there is a tendency to have a false-positive diagnosis of PE, with perfusion only SPECT/CT imaging [9, 25]. In our study, we had 2 cases that were wrongly diagnosed with PE. Their repeat VQ SPECT/CT study performed 3 months after initiating anticoagulation showed matching defects, with no sign of defect resolution. Again, this highlights the importance of the ventilation part of the study, as it improves the specificity of a perfusion only SPECT/CT study.
In our study, 42.9% of the population had associated COVID pneumonia on their CT images. This has been well described in the literature using various reporting patterns [2, 7]. As described earlier, we demonstrated how some of these inflammatory changes in the lungs were associated with increased perfusion. However, in this study, we also observed that 6 (10.7%) of the cases had perfusion defects in areas associated with COVID pneumonia changes (Fig. 11).
We had 2 cases that presented at 3 months after de-isolation, with a false-negative CT pulmonary angiography (CTPA) study. The VQ studies performed on the same day as the CTPA study revealed mismatched perfusion defects in keeping with PE. These 2 cases in particular had persistent respiratory symptoms for over 3 months after de isolation, making chronic PE more likely. The sensitivity of CTPA in the diagnosis of chronic PE is low [13]. This could be the reason why these cases were missed in the CTPA study. It also highlights the potential advantage a VQ study has over a CTPA study performed in this cohort of patients, as a number of them might be investigated in the chronic phase.
Patients with severe COVID-19 infection are likely to be admitted to hospitals, including intensive care units, and placed on prophylactic anticoagulation. They also have a higher chance of being investigated for PE. On the other hand, patients with mild disease are unlikely to be hospitalized and readily investigated for PE. This increases the chances of a missed or delayed diagnosis of PE in this category of patients. We, therefore, recommend that, irrespective of the disease severity or need for hospitalization, all patients with COVID-19 infection, raised D-dimer levels, and persistent or new onset respiratory symptoms need to be further investigated for perfusion abnormalities such as PE. Although the clinical significance of the other causes of perfusion abnormalities in these patients might not be clear, there is a chance that long-term complications might occur if untreated.
We believe that VQ SPECT/CT study is a very good modality in the identification and follow-up of these perfusion abnormalities. The CT portion of the study is also useful in identifying those patients with mosaic attenuation or associated COVID-19 pneumonia. These findings may likely determine the specific management plan for each of these patients.
Some limitations were noted. With a retrospective study design, we could not rule out the existence of some of these lung perfusion abnormalities in our patient population before their COVID-19 infection. We did not identify other possible risk factors for perfusion abnormalities in these patients. We, therefore, recommend that proper prospective studies be carried out in these patients, as this will show the true incidence of perfusion abnormalities in patients with mild COVID 19 infection.