As the COVID-19 pandemic continues, more specialists are becoming aware of fungal co-infections. Aspergillus, candida and mucor are the most common fungi detected so far. Most of the COVID-19 patients did not have a sputum fungal evaluation at the start of their treatment. Also, detecting fungus with a single sputum fungal culture is often difficult [10]. Thus, detection of fungal characteristics on HRCT thorax is a useful tool in this pandemic, because of increasing incidence of superimposed fungal infection.
Diabetes, glucocorticoids, hematopoietic malignancy, persistent neutropenia, hematopoietic stem cell transplantation and trauma are all associated with an increased risk of mucormycosis in COVID-19 patients [11]. In our series, 5 out of 6 patients were diabetics and all patients were on corticosteroid therapy due to COVID infection.
Imaging might be non-specific for the pulmonary mucormycosis. Early imaging may show peri-bronchial GGOs. Subsequently, the illness advances into consolidation or nodules with a CT halo sign, followed by central necrosis and the creation of cavities [12]. The presence of pleural effusion also favours mucor [13]. The reverse halo sign can help distinguish mucor from other fungal pneumonias (like aspergillus) [14]. Case 1 in our presentation, in period of 21 days or less, had developed a large cavitary lesion with soft tissue attenuating growth along the margins of the cavity and this cavitary lesion was formed in the region where two patches of small reverse halo lesions were present in the first CT scan. Because of rapid progression of the small reverse halo lesions into a large cavitation with surrounding consolidation within a short time (~ 21 days), we suspected it to be a fungal lesion. Rapid progression of GGOs into consolidation was also noted. Sputum culture confirmed mucor species. We inferred that the rapidly progressing cavity with soft tissue attenuating growth within, along with surrounding consolidation, was caused by superimposed mucor infection in this COVID patient.
In patient 2, two HRCT scans were done at an interval of 9 days. Initial scan showed cavitary lesions with few smooth internal septations within. Subsequent scan revealed new irregularly margined soft tissue attenuating growth along the walls within the cavity. A new cavity was seen forming in anterior segment of right upper lobe in the region of pre-existing reverse halo lesion. Mucor species grew on sputum culture. Patient was a known case of old pulmonary tuberculosis (PTB). Mucor can form cavities by itself and may show growth within, but in this case due to the absence of previous base line CT scan it was difficult to differentiate mucor from PTB. Even if the cavity was pre-existing due to PTB the new irregular soft tissue attenuating growth along the wall and within the cavity was definitely suggestive of fungal invasion. Moreover, newly formed cavity in pre-existing reverse halo sign favours fungal infestation.
Cases 3 and 4 were recovered COVID patients who were re-admitted due to worsening of symptoms. Both were diabetics. Baseline initial HRCT thorax was not available. CT axial images in case 3 showed multiple cavitary lesions with irregular nodular growth and internal septations, in both lungs, looks like arising from pre-existing reverse halo sign, favouring the fungal infection, came out to be mucor on sputum culture. Large thick walled cavitary lesion with internal septations and fluid level in case 4 strongly suggested fungal aetiology. Minimal right pleural effusion was favouring mucor proved on sputum culture. We infer that a repeat CT scan should be undertaken if already recovered COVID patients again comes with progression or resurgence of symptoms and the presence of cavities on CT should be followed by fungal related investigations.
In severe COVID-19 patients with a broader spectrum of antibacterial medications, parenteral diet and invasive examinations, or in patients with persistent neutropenia and other immune disability causes, the risk of Candida infection may increase dramatically [15]. In our 5th and 6th case, HRCT thorax revealed irregularly margined cavitary lesions within the lungs pointing towards the possibility of fungal infection. Sputum culture revealed Candida species in both of these patients.
After closely observing all the scans of these patients, we infer that it is very difficult to differentiate the superadded fungal infection in COVID patients as GGOs, consolidation and reverse halo signs are commonly seen in both fungal and COVID infections. It becomes more difficult when there is diffuse involvement of lungs in COVID (deviating from the normal peripheral involvement) usually seen in severe patients. However, some clues that can suggest pulmonary fungal infestation are the presence of cavities with soft tissue attenuating irregular growth, pleural effusion and unusual rapid conversion of reverse halo to cavities and consolidation. In patients 1 and 2, new cavities evolved in the region where there were reverse halo lesions in the previous scans; hence in the presence of reverse halo in severe COVID patients with pre-existing risk factors (diabetes and immunocompromised status), a repeat scan in 2–4 weeks or earlier should be the norm.
It is very difficult to differentiate between different invasive fungal species radiologically especially in COVID scenario, as all of them show overlapping radiological features among themselves and with COVID. However, presence of more than 10 nodules with pleural effusion and reverse halo sign is in favour of pulmonary mucormycosis rather than aspergillosis or other fungal infections [13]. Pleural effusion was seen in case 4 of mucormycosis and new cavities were formed in pre-existing reverse halo sign in cases 1, 2 and 3 of mucormycosis. The most common thin-section CT findings of pulmonary candidiasis are multiple bilateral nodular opacities often associated with areas of consolidation [16]. Multiple cavitary lesions with surrounding consolidation may also be seen in pulmonary candidiasis [17]. This was correlating with our findings in cases 5 and 6 of candidiasis. We found that although invasive candidiasis showed cavities, yet their sizes were small and progression was relatively slow. In our study, cases 1, 2, 3 and 4 showed relatively rapid progression of cavities that could be attributed to highly invasive nature of mucor species. In general, pulmonary mucormycosis is rare in comparison with pulmonary aspergillosis and candidiasis, but in this COVID crisis, there is surge in mucor infections due to rampant steroid use and high prevalence of diabetes in countries like India.
We suggest, in severe COVID patients (specially with diabetes and immunosuppressive states), close monitoring and follow-up for the cavitary lesions with CT scan should be undertaken. Appearance of new cavities or soft tissue attenuating growth within existing cavity should be reported as probable fungal infection in this pandemic until proved otherwise and empirical antifungals should be started as soon as possible because the superimposed fungal infection with COVID has significantly higher mortality. Once the diagnosis of pulmonary fungal infection is documented, other organs specially brain and paranasal sinuses should be examined clinically and radiologically as these regions are also commonly affected by fungal species. The most common fungal pathogens associated with CNS infections include candida and aspergillus species, and mucorales fungi [18].
There seems to be a variety of factors that might lead to fungal infections in these four COVID-19 patients: (1) mucormycosis is more likely to occur if diabetes is present. (2) Uncontrolled hyperglycaemia is frequently seen as a result of corticosteroid use. Acidosis causes a low pH, which is ideal for mucor spores to grow. (3) COVID-19 frequently causes endothelialitis, endothelial damage, lymphopenia, thrombosis and a decrease in CD4+ and CD8+ levels, putting the patient at risk for opportunistic fungal infection. (4) For mucormycosis, free iron is a great resource. Hyperglycaemia causes transferrin and ferritin to be glycosylated, which lowers iron binding and allows for more free iron. Furthermore, a rise in cytokines, particularly interleukin-6, increases free iron via raising ferritin levels due to increased synthesis and reduced iron transport in COVID-19 patients. (5) In the setting of diminished WBC phagocytic activity, mucor formation is encouraged by high glucose, low pH, and free iron [19].
Pneumomediastinum and pneumothorax in cases 2 and 5, respectively, were without any iatrogenic cause, leading us to infer that this was a COVID-related complication rather than a result of mechanical or barotrauma [20, 21] The widespread alveolar damage to serious COVID conditions might be one probable mechanism in this case in which alveoli are prone to rupture [21].
Since HRCT thorax has become one of the most widely used diagnostic investigations in COVID patients, identifying radiological characteristics of fungal infection in COVID can thus be a valuable for triaging. In all of our cases, the radiological findings on HRCT thorax prompted the clinicians to rule out fungal infections. It was felt that a HRCT on admission and discharge (10–14 days approximately) and a follow-up scan after 2 to 4 weeks (if the patient showed worsening of symptoms) for analysis by skilful radiologists will be beneficial in picking up early fungal attack, if any, to pick up the effects of this deadly virus early, to avoid treatment delays and enhance the chances of survival.
We could not include imaging features of pulmonary aspergillosis with COVID-19 patients as no case came till writing of this report. This is the limitation of this article.
A recommended protocol for detection of suspicious fungal infection in special categories of COVID patients is given in Fig. 7.