COVID19 pneumonia with cavitation and cystic lung changes: multi-detector computed tomography spectrum of a gamut of etiologies

The COVID19 pandemic since its beginning in March 2020, continues to wreak havoc causing great morbidity and mortality with each passing day. Ample literature is now available describing the imaging features of COVID19 infection; however, there is still a paucity of knowledge on the various causes of pulmonary cavitation and cystic lesions which can be associated with the virus albeit uncommonly. Cavitation in a COVID19 positive patient could be a consequence of the infection itself or a manifestation of sinister etiologies like coinfection with bacterial, fungal or mycobacterial pathogens, or incidental malignancy/metastasis. It could also be a result of multiple cavitating pulmonary nodules as a manifestation of septic emboli and infarct, Granulomatosis with polyangiitis or rheumatoid arthritis creating a diagnostic dilemma. Similarly, the causes of cystic air spaces on chest CT in COVID19 patient can be varied, either primarily due to the infection itself or secondary to coexistent cystic bronchiectasis, emphysema, interstitial lung disease or mechanical ventilation-associated barotrauma as well as complicated pulmonary cysts. Through this pictorial review, we aim to highlight these uncommon imaging manifestations of COVID19 and educate the reader regarding the various causes, MDCT features and differentials to be considered while approaching a cavity/cystic lesion amidst this pandemic.


INTRODUCTION
The novel Coronavirus disease, also known as COVID19 infection first reported in the late 2019, has rapidly spread across the globe and resulted in significant mortality and morbidity.
Because of the pulmonary tropism of the virus, pulmonary manifestations are often encountered in symptomatic patients. Chest CT plays a critical role in the evaluation of COVID19 infection.
The typical CT features include multifocal bilateral rounded ground glass opacities with or without consolidations predominantly in a peripheral and basal distribution with superimposed interlobular septal thickening resulting in a crazy paving pattern. These can resolve/heal with varying degree of fibrosis. 1 Discrete pulmonary nodules, lymphadenopathy, pleural effusion and cavitation have been rarely described. Cavitation and cystic changes have been reported in only about 0.7% of the cases on imaging. 2 Another rare manifestation is the presence of cystic air spaces (tiny air spaces distinct from cavitation), reported in only a few cases.
Cavities and cystic lesions on chest CT in COVID19 infection can occur due to a gamut of etiologies; either primarily due to COVID19 infection or secondary to various coexisting pathologies (Table 1). Though scattered reports are available, to the best of our knowledge, there is no comprehensive article compiling the various causes. The authors encountered 32 COVID19 cases with cysts and/or cavitation on chest CT in a dedicated COVID hospital. This pictorial review encompasses the CT spectrum of the various cavitatory and cystic lesions which can be seen to develop, coexist or be complicated by COVID19 infection. has been observed in the absorption stage of disease, usually after 14 days. Although the exact cause remains unknown, predominant histopathological pulmonary finding seen is diffuse alveolar damage. Cavitation can be associated with worsening of symptoms after an initial recovery and a higher morbidity and mortality.
On imaging, the cavitatory lesions in COVID19 can be single or multiple, are often variable in size and can be bilateral. [3][4][5][6] They occur in areas of peak disease activity, i.e. in regions of previous ground glass opacities or consolidation. 3 These cavities are thick walled, often have an irregular inner wall and can occasionally have an air fluid level. Signs of fibrosis like interlobular septal thickening, fibrotic ground glass opacities, bronchiectasis or parenchymal bands can be seen in the rest of the lung fields as cavitation occurs in the later stage of the disease 4 (Figures 1-4).
Other causes of cavitation like a superadded bacterial, fungal, or mycobacterial infection as well as uncommon causes like a cavitatory infarct, nodule or underlying neoplasm should be excluded by extensive work-up. A comparison with prior imaging can aid in excluding a pre-existing cavity. Serial imaging is mandated to observe any progression or regression of the cavity, and for detection of any complications like pneumothorax.
Cystic air spaces associated with COVID19 Cystic air spaces are small air containing spaces that have been described in a few published reports in association with COVID19 pneumonia. [7][8][9][10][11] Their exact pathogenesis remains unclear although damage to alveolar walls by exudates and physiological dilatation of air spaces have been postulated as causative mechanisms.
On chest CT, these appear as multiple small, thin walled air spaces with smooth inner wall, and have been referred to as vacuolar

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Pictorial review: Imaging spectrum of various cavitatory and cystic lesions with COVID19 sign, 7 air bubble sign 9 or round cystic change. 11 Preferential locations described are subpleural and/or peribronchovascular. 10 In our series, seven cases revealed multiple cystic air spaces, subpleural location was seen in four cases while three cases had cysts within the area of pneumonitis or consolidation and no peribronchovascular cysts were observed. Most cases had cysts in the anterior part of the lung (right middle lobe and lingular segment of left lobe), an observation not previously reported. Intralesional cysts have also been mentioned only in a single previous publication 8 (Figures 4 and 5).
Presence of cysts can increase the specificity of diagnosis as these are not reported with other viral pneumonias although, a differentiation from pre-existing emphysema or interstitial lung disease is essential. Small cystic lesions conforming to areas of prior or current ground glass opacities and consolidations, favor the association with COVID19, while a more random distribution, large and variable size points to other etiologies ( Figure 6).

Cavitation with coexistent COVID19 infection Bacterial coinfections with COVID19 infection
Non-mycobacterial infections: Bacterial coinfections as a result of reduced host immunity in COVID19 have been reported in 7% of hospitalized patients and 14% of ICU patients, 12 and these can adversely impact the prognosis. Commonly isolated bacterial co-pathogens include Streptococcus pneumoniae, K. pneumoniae, M. pneumoniae, H. influenzae and P. aeruginosa. 12 Klebsiella, Staphylococcus and Streptococcus are commonly associated with cavitation. Bacterial coinfections are likely to pose a diagnostic challenge both for the clinician and radiologist. Imaging features atypical for COVID19 like lobar consolidation, pleural effusion,   Axial (a-d) and sagittal (e) lung window sections show patches of consolidation predominantly involving the right lung with multiple variable sized cavities (irregular inner wall and larger size) located within the area of maximal consolidation (red arrow). Also seen are multiple small cystic lesions (smaller with smooth inner wall) in the paraseptal location (yellow arrows). Fibrotic ground glass opacities with interlobular septal thickening with ipsilateral mediastinal shift suggestive of fibrotic sequelae is also present. mediastinal lymphadenopathy and cavitation should prompt the radiologist to consider a bacterial coinfection ( Figure 7).

Mycobacterium tuberculosis coinfections:
In an endemic country like India, coinfection with pulmonary tuberculosis (PTB) in a COVID19 patient is commonly seen and its incidence further increases due to a suppressed cellular immunity and high dose corticosteroid administration in moderate to severe COVID19 infection. The COVID19 patients can either develop primary active tubercular coinfection or superinfection (Figure 8), or there can be a reactivation of previous infection ( Figure 9). Also, COVID19 may be coexistent in a patient with sequelae of previous tubercular infection ( Figure 10). The imaging findings are summarized in Table 2.
Tubercular coinfection can result in a higher probability of a severe and critical COVID19 infection, a delayed recovery, and a higher mortality. Thus, a high index of suspicion is essential, and a prompt testing is warranted. Figure 5. Multiple cystic air spaces in severe COVID19 pneumonia: 53-year-old male with COVID19 infection and severe shortness of breath and low oxygen saturation. Chest radiograph (a) on Day 10, shows multifocal fluffy air space opacities in the bilateral lung fields with an apicobasal gradient. Chest HRCT (axial section a) done on Day 14 of illness shows bilateral diffuse ground glass opacities with interlobular septal thickening. A few cystic air spaces (with regular inner walls) are seen anteriorly in para-septal location (red arrows) (within the middle lobe and lingular segment of left upper lobe) bilaterally. HRCT on Day 24 (c, d) revealed an increase both in number and size of the cystic air spaces (yellow arrows) while the parenchymal changes have become sharper and more organized, although still severe. Figure 6. Emphysematous bullae with cystic air spaces as COVID19 sequelae: 67-year-old smoker and a known case of COPD with COVID19 illness. Axial (a, b, d, e), sagittal (c) and coronal (f) CT sections on Day 20 of illness, show multiple tiny relatively thick-walled cystic air spaces (red arrows) noted both in the subpleural and intralesional location, seen along the distribution of the post-COVID19 fibrotic changes in the bilateral peripheral lung fields. In addition, larger thin-walled emphysematous bullae/blebs are seen in the upper sections of the chest (yellow arrows) largely confined to areas uninvolved with the fibrotic changes. These bullae are possibly due to pre-existing COPD (However, no previous HRCT was available for comparison). COPD, chronic obstructive pulmonary disease. 50-year-old diabetic male with chest tightness and dyspnoea since 10 days, tested positive for COVID19. Imaging on Day 14: frontal chest radiograph (a) revealed marked asymmetrical involvement with infiltrates in the entire right lung and relative sparing of the left lung. HRCT axial section (b) revealed patchy consolidation with few tiny cystic areas within (red arrow). Associated interlobular septal thickening and mild volume loss of right lung was also present. Imaging on Day 32: patient had only slight clinical improvement chest radiograph (c) shows marked ipsilateral mediastinal shift and volume loss with some resolution of infiltrates. HRCT (d) revealed increased size and number of the areas of cavitation which can be seen bilaterally now in areas of previous consolidation (yellow arrow) and were assumed to be a sequelae of COVID19. Imaging on Day 40: patient had clinically worsened Chest radiograph (e) revealed a large cavity in the left lower zone (arrowhead). HRCT (f) revealed marked increase in the size of the cavity in the lingular segment showing thick irregular walls (yellow arrow), disproportionate to the area of previous consolidation, a superinfection was suspected. The features in the right lung remained unchanged. On sputum culture, Klebsiella pneumoniae was isolated. Fungal coinfection with COVID19 infection Fungal coinfection with COVID19 infection is on a rise possibly because of immune dysregulation, increasing use of corticosteroids and more awareness amongst clinicians; COVID19-associated invasive pulmonary aspergillosis (CAPA) infection has been observed in as many as 20-35% of severely ill and immunocompromised patients. 13 Other coexisting fungal lesions were due to subacute pulmonary aspergillosis, 14 Candida, Mucor or Cryptococcal infections. 13 On HRCT, CAPA usually presents as nodules with a halo sign with cavitation being an uncommon finding, while subacute aspergillosis is seen as a fungal ball within a cavity with an aircrescent sign ( Figure 11).
Cavitation secondary to embolism and infarcts COVID19 infection predisposes to pulmonary embolism due to its prothrombotic state which can lead to pulmonary infarcts. On Chest CT, infarcts appear as multiple peripheral wedgeshaped opacities which may show internal cavitation, 15 although uncommon.
Septic emboli can be seen as multiple nodules distributed peripherally, with majority showing a central cavitation and a feeding vessel sign 15 in a background of COVID19 pneumonitis ( Figure 12).

Cavitation due to neoplastic etiology
Primary lung cancer Cavitation can be seen in primary lung cancers in up to 20 percent of the cases with squamous cell being the most common histological type associated with it, followed by adenocarcinoma. On imaging, the cavity typically shows thick irregular walls with a thickness of more than 15 mm associated with a greater   Multiple patchy peripheral ground glass opacities with interlobular septal thickening are also seen predominantly in the basal lower lobes (arrowheads). Coronal chest and abdomen sections (c, f) reveal no significant abnormality to suggest reactivation of tuberculosis; sputum culture and staining was negative for Acid Fast Bacillus.
likelihood of malignancy 16 (Figure 13). Cavitation may also occur in a lung mass secondary to treatment with novel chemotherapeutic agents (like anti angiogenic factors) 17 as well as with radiation therapy, due to central necrosis of the tumor.

Pulmonary metastasis
Pulmonary metastasis typically results in multiple variable sized peripherally located nodules, which can cavitate resulting in thick-walled irregular cavities. Metastasis from squamous cell carcinoma (most common), adenocarcinoma and sarcomas can show cavitation 16 (Figure 14).

Cavitation due to miscellaneous causes
Pulmonary nodules showing cavitation can be seen in Granulomatosis with polyangiitis (Wegener's granulomatosis) -a granulomatous vasculitis which presents as multiple variable sized, peripheral predominant nodules showing cavitation, with often a vessel leading up to it that may be thrombosed. 15 It can be associated with upper respiratory tract and multisystemic manifestations, frequently involving the kidneys (Figure 15). Rheumatoid arthritis (RA) can frequently have lung manifestations in the form of interstitial lung disease or rheumatoid nodules which may show cavitation. 16 Nodular opacities due to embolism, metastasis, Wegener's granulomatosis or RA may be difficult to differentiate from multifocal nodular opacities seen in about 20% cases of COVID19. 1 However, the presence of cavitation should pre-empt a search for any primary malignancy, thrombus or septic foci, or other etiologies.

Cystic lung lesions with coexistent COVID19 infection Pneumothorax: mechanical ventilation associated barotrauma/Spontaneous
Pneumothorax and pneumomediastinum in COVID19 is often seen either due to mechanical ventilation associated barotrauma or spontaneously. 18 On imaging, a contained pneumothorax can mimic a cavitatory lesion, appearing as a well-defined lucency without bronchovascular markings. However, compression of surrounding lung parenchyma and displaced visceral pleural line help in differentiation and suggest pneumothorax ( Figure 16).

Cystic bronchiectasis
Bronchiectasis can occur due to a variety of conditions including -sequelae of COVID19 related fibrosis, previous infections including mycobacterium tuberculosis, cystic fibrosis and various ciliary dyskinesias. 15 The distribution (craniocaudal, peripheral or central) and associated findings help to point to the cause of bronchiectasis. Tractional bronchiectasis at the sites of previous consolidation or ground glass opacities with other signs of fibrosis in a patient with history of previous or current COVID19 infection can suggest post-COVID19 bronchiectasis, whereas asymmetrical upper lobe bronchiectasis with volume loss and calcified granulomas in an endemic nation can be suggestive of post-tubercular bronchiectasis (Figures 17-20).

Emphysematous bullae
Emphysematous bullae can be encountered in a COVID19 positive patient on chest CT and can mimic cystic air spaces  associated with COVID19 pneumonia. Bulla appears as an air lucency (>1 cm size) with thin imperceptible walls 15 usually having an apical or subpleural, as well as a centrilobular location, with other features of emphysema like low attenuation areas and vascular pruning. Cystic air spaces associated with COVID19 on the other hand, have a non-random distribution and are usually confined to areas of COVID19 pneumonitis ( Figure 6).

Solitary cyst or pneumatocoele
Lung cysts or pneumatocoeles have been reported to be associated with COVID19 infection in areas of ground glass opacities. 11 These are often solitary and larger unlike cystic air spaces which are multiple and smaller ( Figure 21).

Honeycombing -usual interstitial pneumonia
Usual interstitial pneumonia (UIP) can result in pulmonary fibrosis causing multiple thin-walled cysts stacked in contiguous      However, on contiguous sections (d) it was observed to be communicating with the trachea-bronchial tree suggestive of cystic bronchiectasis, which was also seen involving the posterior segment of right upper lobe. Multiple patchy peripheral subpleural consolidations are seen in the left lower lobe suggestive of COVID19 pneumonitis. Figure 21. Simple cyst/pneumatocele with pneumomediastinum and subcutaneous emphysema in severe COVID19 pneumonitis: 53-year-old male with severe COVID19 infection and persistently low saturation necessitating invasive mechanical ventilation. Axial (a, b) and coronal (c) lung window sections on Day 21 of illness show a well-defined oval to round thin-walled simple cyst (red arrow) in the anterior segment of right upper lobe in a background of diffuse ground glass opacities and interlobular septal thickening. Note is made of endotracheal tube in situ with associated pneumomediastinum and subcutaneous emphysema suggesting barotrauma associated changes. Figure 22. Usual Interstitial Pneumonia with COVID19 infection: 45-year-old female, a known case of UIP was diagnosed with COVID19 infection. Chest HRCT axial sections (a, b, d, e) show peripheral patchy consolidations predominantly in the posterior segments (red arrows). Also seen in marked bilateral basal predominant honeycombing (yellow arrows) and interlobular septal thickening. Coronal reformatted sections (c and f) demonstrate the basal gradient of the honeycombing (characteristic of UIP) and the peripheral patchy consolidations due to COVID19 pneumonitis. UIP, usual interstitial pneumonia.