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The rising burden of invasive fungal infections in COVID-19, can structured CT thorax change the game

The rising burden of invasive fungal infections in COVID-19, can structured CT thorax change the... Background: The occurrence of invasive fungal infections in COVID-19 patients is on surge in countries like India. Several reports related to rhino-nasal-sinus mucormycosis in COVID patients have been published in recent times; however, very less has been reported about invasive pulmonary fungal infections caused mainly by mucor, aspergillus or invasive candida species. We aimed to present 6 sputum culture proved cases of invasive pulmonary fungal infec- tion (four mucormycosis and two invasive candidiasis) in COVID patients, the clues for the diagnosis of fungal invasion as well as difficulties in diagnosing it due to superimposed COVID imaging features. Case presentation: The HRCT imaging features of the all 6 patients showed signs of fungal invasion in the form of cavities formation in the pre-existing reverse halo lesions or development of new irregular margined soft tissue attenuating growth within the pre-existing or in newly formed cavities. Five out of six patients were diabetics. Cavities in cases 1, 2, 3 and 4 of mucormycosis were aggressive and relatively larger and showed relatively faster progression into cavities in comparison with cases 5 and 6 of invasive candidiasis. Conclusion: In poorly managed diabetics or with other immunosuppressed conditions, invasive fungal infection (mucormycosis, invasive aspergillosis and invasive candidiasis) should be considered in the differential diagnosis of cavitary lung lesions. Keywords: Pulmonary fungal infections, Mucormycosis, Invasive candidiasis Background Lung involvement with mucormycosis often deprived of The victims of COVID-19 are incredibly prone to fungal an early specific treatment because of delay in diagno - and bacterial infections, especially those in an intensive sis. High-resolution computed tomography (HRCT) of care unit (ICU). Aspergillosis, invasive candidiasis and thorax plays an important role in detecting the varied mucormycosis are the most common associates [1–6]. features of this dreadful condition early, if a follow-up The occurrence of these fungal co-infections is rising [1, scan for COVID-19 patients is undertaken in about ten 3, 4, 7, 8]. The disease is usually associated with comor - days or as per protocol or HRCT undertaken in patients bidities like haematologic malignancy, diabetes and with chest infection and breathlessness with pre-existing impaired immunological systems [9]. Mucormycosis fre- risk factors and co-morbidities during this pandemic quently affects the sinus, brain and respiratory system. situation. We are presenting six cases of COVID-19, who devel- oped invasive pulmonary fungal infection, four of them were mucor and remaining two were of candida spe- *Correspondence: Roopak21dubey@gmail.com Department of Radio-Diagnosis, Kalinga Institute of Medical Sciences, KIIT cies. We have also tried to set a protocol for undertaking Road, Patia, , Bhubaneswar, Odisha 751024, India © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Dubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 2 of 10 HRCT chest, for early detection of any associated pulmo- sliding scale. Despite receiving the required therapy, his nary fungal infection in COVID patients. health worsened over the next few days. This necessi - tated the need for a repeat CT scan. Which was done Case presentation on 21st day. Scan revealed diffuse GGOs along with Case 1 interlobular septal thickening in all lobes and a large A 55-year-old male patient presented with pyrexia, thick walled cavitary lesion surrounded by consolida- tachypnea, severe breathlessness and sore throat for tion in left upper lobe. Curvilinear soft tissue density 4  days. He was reverse-transcriptase polymerase chain growth within irregular margins was noted within the reaction (RT-PCR) positive. He was a known diabetic cavity, indicating a high possibility of fungal infection being managed with oral hypoglycaemic drugs. Com- (Fig. 1). plete blood count revealed a haemoglobin level of 11 gm/ Sputum samples were then collected and sent for dl, lymphopenia (10%; normal 20–40%). high C-reactive fungal culture which was positive for mucormycosis. protein (CRP)—29.53 mg/l, high procalcitonin—0.89 ng/ Antibiotic susceptibility showed sensitivity to ampho- ml, elevated D-dimer assay. HRCT scan of the chest was tericin B and voriconazole, while fluconazole showed done on 2nd day of admission, showed diffuse ground- intermediate sensitivity. Culture revealed insensitivity glass opacities (GGO) in both lungs with patchy consoli- to caspofungin. dations and reverse halo sign. CT severity score of 22/25 Another repeat scan was done on 30th day in order (typical for COVID-19). to track the progression of fungal infestation, showing During the course of his hospital stay, he was treated no obvious change in characteristic of left upper lobar with intravenous antibiotics, steroids, anti-viral and lesion. Patient became RTPCR negative on 32nd day multivitamins, as well as general supportive care. To and was shifted to high dependency unit (HDU) for avoid thrombotic problems, he was also given subcuta- further management. At the time of writing, he was on neous enoxaparin (40  mg/0.4  ml) twice a day. His dia- aggressive antifungals and antibiotics. betes was controlled with insulin doses adjusted on a Fig. 1 Imaging features of mucormycosis in Case 1 of COVID-19. A, B Axial HRCT scans show diffuse ground glass opacities in bilateral lung fields with few patches of reverse halo lesions (yellow arrow in A), without any evidence of cavitation. The scan was repeated after 21 days revealed cavitary lesions with soft tissue attenuating irregularly margined growth suggesting fungal infestation (orange arrow in B). C, D Revealed rapid progression of GGOs into consolidation (Green arrow in D) D ubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 3 of 10 Case 2 ill-defined ground glass opacities were also noted in both A 32-year-old male was admitted with fever and cough lungs along with minimal right pleural effusion (Fig.  4). for 6  days. He had completed anti-tubercular treatment On the basis of CT report, sputum culture was done (ATT) in the past and was a known diabetic (5  years) which revealed mucor species. At the time of writing, the with chronic kidney disease (CKD) on medical manage- patient was in ICU and on antifungals and antibiotics as ment. D-Dimer and CRP were elevated. The patient was per recommendation by antibiotic susceptibility test. managed conservatively with oxygen, intravenous anti- biotics, injection dexamethasone and injection enoxapa- Case 5 rin. CT chest done on the 3rd day of admission, revealed A 52-year-old RTPCR positive male patient was admit- fibro-cavitary lesions, bilateral patchy consolidation with ted with complaints of fever, burning micturition and traction bronchiectatic changes in left lung. Some of the multiple joint pain since two months. Patient was a non- cavities showed fluid level. Fibro-cavitary lesion and ill- diabetic and without any other comorbidities. He was defined ground glass opacities were seen in left lower discharged after 4  days, advised home quarantine with lobe. Pneumo-mediastinum was also noted (Fig.  2). oral medications. In next few days, the oxygen requirement gradually Patient was readmitted after 1  month with breathless- increased and he developed severe respiratory distress ness, sore throat and cough. HRCT thorax revealed col- with repeated desaturation for which he was admitted lapse and consolidation with diffuse GGOs in all lobes of in ICU for respiratory support. Another CT scan was bilateral lung fields. Bilateral pneumothorax (right > left) undertaken on the 9th day which revealed irregularly was also noted. Irregularly marginated cavitary lesion margined soft tissue attenuating structures, develop- seen in right middle lobe with few internal septations ing within the pre-existing cavities and some with fluid pointing towards the possibility of fungal infection within levels suggesting a fresh growth (Fig. 2). Culture for fun- the cavity (Fig. 5). gal infection was advocated on the basis of CT report. Sputum for acid fast bacilli was negative. Sputum for The sputum culture revealed mucormycosis for which gram staining showed few epithelial cells, few gram- amphotericin B was started. However, despite best efforts positive cocci and plenty of gram-positive budding yeast the patient succumbed to death on the 14th day. cells with pseudohyphae. Culture for the fungal infec- tion revealed candida tropicalis with amphotericin B and fluconazole resistivity and caspofungin, flucytosine and Case 3 micafungin sensitivity. Voriconazole showed intermedi- A 55-year-old COVID recovered patient came to our ate sensitivity. hospital after 15  days of discharge from another hospi- tal. RTPCR for COVID virus came negative at the time of Case 6 admission. He was a known diabetic patient and showing A 45-year-old man, RTPCR positive, was admitted with worsening of symptoms (breathlessness and cough) since complaints of fever cough and breathlessness for 3 days. last few days. His CRP was deranged and CBC revealed He was a known diabetic since 10  years. At the time of lymphopenia. HRCT thorax revealed multiple large cavi- admission, CRP and D-dimer were raised significantly. tary lesions surrounded by ground glass opacities and He was managed with COVID protocol. HRCT thorax consolidation in both lungs (Fig.  3). Thin internal septa - revealed patchy areas GGOs, consolidations with some tions were noted in the cavities. Initial baseline CT scan areas of interlobular septal thickening seen bilaterally. of patient was unavailable. Sputum culture of patient Multiple areas of cavitary changes were seen in bilateral revealed mucor growth. At the time of writing, he was in upper lobes and right middle lobe. Some of the cavities critical condition and on antifungals and antibiotics. showed irregular soft tissue density structures within, suggesting a fungal growth (Fig. 6). Sputum culture grew Case 4 candida albicans with amphotericin B, caspofungin, flu - A 74-year-old elderly male admitted to our hospital after conazole, flucytosine, micafungin sensitivity and voricon - recovering from COVID-19. He was a known diabetic azole resistivity. since 20  years. As the per the available information, he took the treatment from some other hospital includ- Discussion ing 8  mg injections of steroids twice a day. Initial base- As the COVID-19 pandemic continues, more specialists line scan was unavailable. HRCT thorax done in our are becoming aware of fungal co-infections. Aspergillus, hospital revealed large thick walled cavitary lesion with candida and mucor are the most common fungi detected internal septations and fluid level in the right lower lobe, so far. Most of the COVID-19 patients did not have a suspicious of invasive fungal aetiology. Patchy areas of sputum fungal evaluation at the start of their treatment. Dubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 4 of 10 Fig. 2 Axial HRCT scans showing imaging features of mucormycosis in case 2 of COVID-19. A–D CT axial images A and C show multiple cavitary lesions in the left upper and lower lobes. The repeat scans B and D show soft tissue attenuating growth (yellow arrows in B and D). Mild pneumomediastinum (red arrow in C) also noted. E, F A new cavity formed in the right upper lobe (green arrow in F) in pre-existing reverse halo sign (orange arrow in E). G, H Multiple soft tissue nodular opacities developed especially in left lower lobe in H in comparison with G D ubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 5 of 10 Fig. 3 Axial HRCT scans showing imaging features of Mucormycosis in Case 3 of COVID-19. CT axial images shows multiple cavitary lesions with irregular nodular growth and internal septations, in both lungs, look like arising from pre-existing reverse halo sign Also, detecting fungus with a single sputum fungal cul- time (~ 21  days), we suspected it to be a fungal lesion. ture is often difficult [10]. Thus, detection of fungal Rapid progression of GGOs into consolidation was also characteristics on HRCT thorax is a useful tool in this noted. Sputum culture confirmed mucor species. We pandemic, because of increasing incidence of superim- inferred that the rapidly progressing cavity with soft tis- posed fungal infection. sue attenuating growth within, along with surrounding Diabetes, glucocorticoids, hematopoietic malig- consolidation, was caused by superimposed mucor infec- nancy, persistent neutropenia, hematopoietic stem cell tion in this COVID patient. transplantation and trauma are all associated with an In patient 2, two HRCT scans were done at an inter- increased risk of mucormycosis in COVID-19 patients val of 9  days. Initial scan showed cavitary lesions with [11]. In our series, 5 out of 6 patients were diabetics and few smooth internal septations within. Subsequent scan all patients were on corticosteroid therapy due to COVID revealed new irregularly margined soft tissue attenuat- infection. ing growth along the walls within the cavity. A new cav- Imaging might be non-specific for the pulmonary ity was seen forming in anterior segment of right upper mucormycosis. Early imaging may show peri-bronchial lobe in the region of pre-existing reverse halo lesion. GGOs. Subsequently, the illness advances into consolida- Mucor species grew on sputum culture. Patient was a tion or nodules with a CT halo sign, followed by central known case of old pulmonary tuberculosis (PTB). Mucor necrosis and the creation of cavities [12]. The presence of can form cavities by itself and may show growth within, pleural effusion also favours mucor [13]. The reverse halo but in this case due to the absence of previous base line sign can help distinguish mucor from other fungal pneu- CT scan it was difficult to differentiate mucor from PTB. monias (like aspergillus) [14]. Case 1 in our presentation, Even if the cavity was pre-existing due to PTB the new in period of 21  days or less, had developed a large cavi- irregular soft tissue attenuating growth along the wall tary lesion with soft tissue attenuating growth along the and within the cavity was definitely suggestive of fungal margins of the cavity and this cavitary lesion was formed invasion. Moreover, newly formed cavity in pre-existing in the region where two patches of small reverse halo reverse halo sign favours fungal infestation. lesions were present in the first CT scan. Because of rapid Cases 3 and 4 were recovered COVID patients who progression of the small reverse halo lesions into a large were re-admitted due to worsening of symptoms. Both cavitation with surrounding consolidation within a short were diabetics. Baseline initial HRCT thorax was not Dubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 6 of 10 Fig. 4 Axial HRCT scans showing imaging features of Mucormycosis in Case 4 of COVID-19. 4 A, B CT axial image large cavitary lesions (yellow arrow in A) with thick internal septations, surrounded by thick consolidation. Dense consolidation also noted in left lower lobe (orange arrow in B). C Air fluid level within cavity (green arrow in C). D Minimal right pleural effusion (dark orange arrow in D) Fig. 5 Axial HRCT scans showing imaging features of Candidiasis in case 5 of COVID-19. A Axial HRCT thorax of case 5 shows small cavitary lesions with few internal septations and tiny soft tissue nodular opacities within (yellow arrow in A). Sputum culture revealed Candida species. B Bilateral pneumothorax can be seen (orange arrows in B) available. CT axial images in case 3 showed multiple walled cavitary lesion with internal septations and fluid cavitary lesions with irregular nodular growth and inter- level in case 4 strongly suggested fungal aetiology. Mini- nal septations, in both lungs, looks like arising from pre- mal right pleural effusion was favouring mucor proved existing reverse halo sign, favouring the fungal infection, on sputum culture. We infer that a repeat CT scan should came out to be mucor on sputum culture. Large thick be undertaken if already recovered COVID patients again D ubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 7 of 10 Fig. 6 Axial HRCT images of case 6 shows multiple cavitary lesions in both lungs with irregularly margined soft tissue attenuation nodular growth. Sputum culture revealed Candida species comes with progression or resurgence of symptoms and patients with pre-existing risk factors (diabetes and the presence of cavities on CT should be followed by fun- immunocompromised status), a repeat scan in 2–4 weeks gal related investigations. or earlier should be the norm. In severe COVID-19 patients with a broader spectrum It is very difficult to differentiate between differ - of antibacterial medications, parenteral diet and invasive ent invasive fungal species radiologically especially in examinations, or in patients with persistent neutropenia COVID scenario, as all of them show overlapping radi- and other immune disability causes, the risk of Candida ological features among themselves and with COVID. infection may increase dramatically [15]. In our 5th and However, presence of more than 10 nodules with pleu- 6th case, HRCT thorax revealed irregularly margined ral effusion and reverse halo sign is in favour of pulmo - cavitary lesions within the lungs pointing towards the nary mucormycosis rather than aspergillosis or other possibility of fungal infection. Sputum culture revealed fungal infections [13]. Pleural effusion was seen in case Candida species in both of these patients. 4 of mucormycosis and new cavities were formed in pre- After closely observing all the scans of these patients, existing reverse halo sign in cases 1, 2 and 3 of mucor- we infer that it is very difficult to differentiate the super - mycosis. The most common thin-section CT findings added fungal infection in COVID patients as GGOs, of pulmonary candidiasis are multiple bilateral nodular consolidation and reverse halo signs are commonly seen opacities often associated with areas of consolidation in both fungal and COVID infections. It becomes more [16]. Multiple cavitary lesions with surrounding consoli- difficult when there is diffuse involvement of lungs in dation may also be seen in pulmonary candidiasis [17]. COVID (deviating from the normal peripheral involve- This was correlating with our findings in cases 5 and 6 of ment) usually seen in severe patients. However, some candidiasis. We found that although invasive candidiasis clues that can suggest pulmonary fungal infestation showed cavities, yet their sizes were small and progres- are the presence of cavities with soft tissue attenuating sion was relatively slow. In our study, cases 1, 2, 3 and 4 irregular growth, pleural effusion and unusual rapid con - showed relatively rapid progression of cavities that could version of reverse halo to cavities and consolidation. In be attributed to highly invasive nature of mucor species. patients 1 and 2, new cavities evolved in the region where In general, pulmonary mucormycosis is rare in compari- there were reverse halo lesions in the previous scans; son with pulmonary aspergillosis and candidiasis, but in hence in the presence of reverse halo in severe COVID this COVID crisis, there is surge in mucor infections due Dubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 8 of 10 Fig. 7 Recommended protocol for triaging the COVID patients with suspicious pulmonary fungal infection to rampant steroid use and high prevalence of diabetes in and radiologically as these regions are also commonly countries like India. affected by fungal species. The most common fungal We suggest, in severe COVID patients (specially with pathogens associated with CNS infections include can- diabetes and immunosuppressive states), close monitor- dida and aspergillus species, and mucorales fungi [18]. ing and follow-up for the cavitary lesions with CT scan There seems to be a variety of factors that might lead should be undertaken. Appearance of new cavities or soft to fungal infections in these four COVID-19 patients: (1) tissue attenuating growth within existing cavity should mucormycosis is more likely to occur if diabetes is pre- be reported as probable fungal infection in this pan- sent. (2) Uncontrolled hyperglycaemia is frequently seen demic until proved otherwise and empirical antifungals as a result of corticosteroid use. Acidosis causes a low should be started as soon as possible because the super- pH, which is ideal for mucor spores to grow. (3) COVID- imposed fungal infection with COVID has significantly 19 frequently causes endothelialitis, endothelial damage, higher mortality. Once the diagnosis of pulmonary fun- lymphopenia, thrombosis and a decrease in CD4+ and gal infection is documented, other organs specially brain CD8+ levels, putting the patient at risk for opportun- and paranasal sinuses should be examined clinically istic fungal infection. (4) For mucormycosis, free iron D ubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 9 of 10 is a great resource. Hyperglycaemia causes transferrin scanning in COVID hospitals will go a long way in saving and ferritin to be glycosylated, which lowers iron bind- patients. ing and allows for more free iron. Furthermore, a rise in cytokines, particularly interleukin-6, increases free iron Abbreviations via raising ferritin levels due to increased synthesis and HRCT : High-resolution computed tomography; RT-PCR: Reverse transcriptase reduced iron transport in COVID-19 patients. (5) In the polymerase chain reaction; GGO: Ground-glass opacities; CKD: Chronic kidney disease; CRP: C-reactive protein; ICU: Intensive care unit; PTB: Pulmonary setting of diminished WBC phagocytic activity, mucor tuberculosis. formation is encouraged by high glucose, low pH, and free iron [19]. Acknowledgements None. Pneumomediastinum and pneumothorax in cases 2 and 5, respectively, were without any iatrogenic cause, Authors’ contributions leading us to infer that this was a COVID-related compli- RD was involved in manuscript formation and analysis. KKS helped in manu- script analysis. SSM contributed to manuscript analysis. SP was involved in cation rather than a result of mechanical or barotrauma manuscript analysis. MG helped in data collection. SMM contributed to data [20, 21] The widespread alveolar damage to serious collection. All authors have read and approved the manuscript. COVID conditions might be one probable mechanism in Funding this case in which alveoli are prone to rupture [21]. None. Since HRCT thorax has become one of the most widely used diagnostic investigations in COVID Availability of data and materials The data were retrieved from our clinical and radiological database. patients, identifying radiological characteristics of fun- gal infection in COVID can thus be a valuable for tri- Declarations aging. In all of our cases, the radiological findings on HRCT thorax prompted the clinicians to rule out fun- Ethics approval and consent to participate gal infections. It was felt that a HRCT on admission and Ethical committee approval and consent has been taken for research purpose. discharge (10–14  days approximately) and a follow-up Consent for publication scan after 2 to 4  weeks (if the patient showed worsen- Appropriate written consent was taken from patient and/or relatives. ing of symptoms) for analysis by skilful radiologists will Competing interests be beneficial in picking up early fungal attack, if any, to The authors declare that they have no competing interests. pick up the effects of this deadly virus early, to avoid treatment delays and enhance the chances of survival. Received: 8 July 2021 Accepted: 30 December 2021 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. References A recommended protocol for detection of suspicious 1. Hoenigl M (2020) Invasive fungal disease complicating COVID-19: when it rains it pours. Clin Infect Dis 73:e1645–e1648 fungal infection in special categories of COVID patients 2. Garcia-Vidal C, Sanjuan G, Moreno-García E, Puerta-Alcalde P, Garcia- is given in Fig. 7. Pouton N, Chumbita M, Fernandez-Pittol M, Pitart C, Inciarte A, Bodro M, Morata L (2021) Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study. Clin Microbiol Infect 27(1):83–88 Conclusion 3. Lansbury L, Lim B, Baskaran V, Lim WS (2020) Co-infections in people with Fungal co-infections linked to COVID-19 may be over- COVID-19: a systematic review and meta-analysis. J Infect 81(2):266–275 4. Gangneux JP, Bougnoux ME, Dannaoui E, Cornet M, Zahar JR (2020) Inva- looked or often misdiagnosed. In India, an unfortunate sive fungal diseases during COVID-19: We should be prepared. J Mycol combination of diabetes, widespread corticosteroid Med 30(2):100971 usage, and uncontrolled adverse effects of COVID-19 5. Song G, Liang G, Liu W (2020) Fungal co-infections associated with global COVID-19 pandemic: a clinical and diagnostic perspective from China. (cytokine storm, endotheliitis, lymphopenia) appears to Mycopathologia 185:1–8 be increasing the risk of fungal infections. 6. Koehler P, Cornely OA, Böttiger BW, Dusse F, Eichenauer DA, Fuchs F, Most COVID patients undergo a HRCT thorax at some Hallek M, Jung N, Klein F, Persigehl T, Rybniker J, Kochanek M, Böll B, Shimabukuro-Vornhagen A (2020) COVID-19 associated pulmonary point. Hence, an alert skilful radiologist will pick up the aspergillosis. Mycoses 63(6):528–534. https:// doi. org/ 10. 1111/ myc. 13096 characters of the residual lesion and association of this 7. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei deadly virus early. 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Radiographics 40(3):656–666 14. Wahba H, Truong MT, Lei X, Kontoyiannis DP, Marom EM (2008) Reversed halo sign in invasive pulmonary fungal infections. Clin Infect Dis 46(11):1733–1737 15. Clancy CJ, Nguyen MH (2018) Diagnosing invasive candidiasis. J Clin Microbiol 56(5):e01909-e1917 16. Franquet T, Müller NL, Lee KS, Oikonomou A, Flint JD (2005) Pulmonary candidiasis after hematopoietic stem cell transplantation: thin-section CT findings. Radiology 236(1):332–337 17. Yasuda Y, Tobino K, Asaji M, Yamaji Y, Tsuruno K (2015) Invasive candidi- asis presenting multiple pulmonary cavitary lesions on chest computed tomography. Multidiscip Respir Med 10(1):1–3 18. Orlowski HL, McWilliams S, Mellnick VM, Bhalla S, Lubner MG, Pickhardt PJ, Menias CO (2017) Imaging spectrum of invasive fungal and fungal-like infections. Radiographics 37(4):1119–1134 19. Baldin C, Ibrahim AS (2017) Molecular mechanisms of mucormycosis— the bitter and the sweet. PLoS Pathog 13(8):e1006408 20. Zhou C, Gao C, Xie Y, Xu M (2020) COVID-19 with spontaneous pneumo- mediastinum. Lancet Infect Dis 20(4):510 21. Sun R, Liu H, Wang X (2020) Mediastinal emphysema, giant bulla, and pneumothorax developed during the course of COVID-19 pneumonia. Korean J Radiol 21(5):541 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Egyptian Journal of Radiology and Nuclear Medicine Springer Journals

The rising burden of invasive fungal infections in COVID-19, can structured CT thorax change the game

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Abstract

Background: The occurrence of invasive fungal infections in COVID-19 patients is on surge in countries like India. Several reports related to rhino-nasal-sinus mucormycosis in COVID patients have been published in recent times; however, very less has been reported about invasive pulmonary fungal infections caused mainly by mucor, aspergillus or invasive candida species. We aimed to present 6 sputum culture proved cases of invasive pulmonary fungal infec- tion (four mucormycosis and two invasive candidiasis) in COVID patients, the clues for the diagnosis of fungal invasion as well as difficulties in diagnosing it due to superimposed COVID imaging features. Case presentation: The HRCT imaging features of the all 6 patients showed signs of fungal invasion in the form of cavities formation in the pre-existing reverse halo lesions or development of new irregular margined soft tissue attenuating growth within the pre-existing or in newly formed cavities. Five out of six patients were diabetics. Cavities in cases 1, 2, 3 and 4 of mucormycosis were aggressive and relatively larger and showed relatively faster progression into cavities in comparison with cases 5 and 6 of invasive candidiasis. Conclusion: In poorly managed diabetics or with other immunosuppressed conditions, invasive fungal infection (mucormycosis, invasive aspergillosis and invasive candidiasis) should be considered in the differential diagnosis of cavitary lung lesions. Keywords: Pulmonary fungal infections, Mucormycosis, Invasive candidiasis Background Lung involvement with mucormycosis often deprived of The victims of COVID-19 are incredibly prone to fungal an early specific treatment because of delay in diagno - and bacterial infections, especially those in an intensive sis. High-resolution computed tomography (HRCT) of care unit (ICU). Aspergillosis, invasive candidiasis and thorax plays an important role in detecting the varied mucormycosis are the most common associates [1–6]. features of this dreadful condition early, if a follow-up The occurrence of these fungal co-infections is rising [1, scan for COVID-19 patients is undertaken in about ten 3, 4, 7, 8]. The disease is usually associated with comor - days or as per protocol or HRCT undertaken in patients bidities like haematologic malignancy, diabetes and with chest infection and breathlessness with pre-existing impaired immunological systems [9]. Mucormycosis fre- risk factors and co-morbidities during this pandemic quently affects the sinus, brain and respiratory system. situation. We are presenting six cases of COVID-19, who devel- oped invasive pulmonary fungal infection, four of them were mucor and remaining two were of candida spe- *Correspondence: Roopak21dubey@gmail.com Department of Radio-Diagnosis, Kalinga Institute of Medical Sciences, KIIT cies. We have also tried to set a protocol for undertaking Road, Patia, , Bhubaneswar, Odisha 751024, India © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Dubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 2 of 10 HRCT chest, for early detection of any associated pulmo- sliding scale. Despite receiving the required therapy, his nary fungal infection in COVID patients. health worsened over the next few days. This necessi - tated the need for a repeat CT scan. Which was done Case presentation on 21st day. Scan revealed diffuse GGOs along with Case 1 interlobular septal thickening in all lobes and a large A 55-year-old male patient presented with pyrexia, thick walled cavitary lesion surrounded by consolida- tachypnea, severe breathlessness and sore throat for tion in left upper lobe. Curvilinear soft tissue density 4  days. He was reverse-transcriptase polymerase chain growth within irregular margins was noted within the reaction (RT-PCR) positive. He was a known diabetic cavity, indicating a high possibility of fungal infection being managed with oral hypoglycaemic drugs. Com- (Fig. 1). plete blood count revealed a haemoglobin level of 11 gm/ Sputum samples were then collected and sent for dl, lymphopenia (10%; normal 20–40%). high C-reactive fungal culture which was positive for mucormycosis. protein (CRP)—29.53 mg/l, high procalcitonin—0.89 ng/ Antibiotic susceptibility showed sensitivity to ampho- ml, elevated D-dimer assay. HRCT scan of the chest was tericin B and voriconazole, while fluconazole showed done on 2nd day of admission, showed diffuse ground- intermediate sensitivity. Culture revealed insensitivity glass opacities (GGO) in both lungs with patchy consoli- to caspofungin. dations and reverse halo sign. CT severity score of 22/25 Another repeat scan was done on 30th day in order (typical for COVID-19). to track the progression of fungal infestation, showing During the course of his hospital stay, he was treated no obvious change in characteristic of left upper lobar with intravenous antibiotics, steroids, anti-viral and lesion. Patient became RTPCR negative on 32nd day multivitamins, as well as general supportive care. To and was shifted to high dependency unit (HDU) for avoid thrombotic problems, he was also given subcuta- further management. At the time of writing, he was on neous enoxaparin (40  mg/0.4  ml) twice a day. His dia- aggressive antifungals and antibiotics. betes was controlled with insulin doses adjusted on a Fig. 1 Imaging features of mucormycosis in Case 1 of COVID-19. A, B Axial HRCT scans show diffuse ground glass opacities in bilateral lung fields with few patches of reverse halo lesions (yellow arrow in A), without any evidence of cavitation. The scan was repeated after 21 days revealed cavitary lesions with soft tissue attenuating irregularly margined growth suggesting fungal infestation (orange arrow in B). C, D Revealed rapid progression of GGOs into consolidation (Green arrow in D) D ubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 3 of 10 Case 2 ill-defined ground glass opacities were also noted in both A 32-year-old male was admitted with fever and cough lungs along with minimal right pleural effusion (Fig.  4). for 6  days. He had completed anti-tubercular treatment On the basis of CT report, sputum culture was done (ATT) in the past and was a known diabetic (5  years) which revealed mucor species. At the time of writing, the with chronic kidney disease (CKD) on medical manage- patient was in ICU and on antifungals and antibiotics as ment. D-Dimer and CRP were elevated. The patient was per recommendation by antibiotic susceptibility test. managed conservatively with oxygen, intravenous anti- biotics, injection dexamethasone and injection enoxapa- Case 5 rin. CT chest done on the 3rd day of admission, revealed A 52-year-old RTPCR positive male patient was admit- fibro-cavitary lesions, bilateral patchy consolidation with ted with complaints of fever, burning micturition and traction bronchiectatic changes in left lung. Some of the multiple joint pain since two months. Patient was a non- cavities showed fluid level. Fibro-cavitary lesion and ill- diabetic and without any other comorbidities. He was defined ground glass opacities were seen in left lower discharged after 4  days, advised home quarantine with lobe. Pneumo-mediastinum was also noted (Fig.  2). oral medications. In next few days, the oxygen requirement gradually Patient was readmitted after 1  month with breathless- increased and he developed severe respiratory distress ness, sore throat and cough. HRCT thorax revealed col- with repeated desaturation for which he was admitted lapse and consolidation with diffuse GGOs in all lobes of in ICU for respiratory support. Another CT scan was bilateral lung fields. Bilateral pneumothorax (right > left) undertaken on the 9th day which revealed irregularly was also noted. Irregularly marginated cavitary lesion margined soft tissue attenuating structures, develop- seen in right middle lobe with few internal septations ing within the pre-existing cavities and some with fluid pointing towards the possibility of fungal infection within levels suggesting a fresh growth (Fig. 2). Culture for fun- the cavity (Fig. 5). gal infection was advocated on the basis of CT report. Sputum for acid fast bacilli was negative. Sputum for The sputum culture revealed mucormycosis for which gram staining showed few epithelial cells, few gram- amphotericin B was started. However, despite best efforts positive cocci and plenty of gram-positive budding yeast the patient succumbed to death on the 14th day. cells with pseudohyphae. Culture for the fungal infec- tion revealed candida tropicalis with amphotericin B and fluconazole resistivity and caspofungin, flucytosine and Case 3 micafungin sensitivity. Voriconazole showed intermedi- A 55-year-old COVID recovered patient came to our ate sensitivity. hospital after 15  days of discharge from another hospi- tal. RTPCR for COVID virus came negative at the time of Case 6 admission. He was a known diabetic patient and showing A 45-year-old man, RTPCR positive, was admitted with worsening of symptoms (breathlessness and cough) since complaints of fever cough and breathlessness for 3 days. last few days. His CRP was deranged and CBC revealed He was a known diabetic since 10  years. At the time of lymphopenia. HRCT thorax revealed multiple large cavi- admission, CRP and D-dimer were raised significantly. tary lesions surrounded by ground glass opacities and He was managed with COVID protocol. HRCT thorax consolidation in both lungs (Fig.  3). Thin internal septa - revealed patchy areas GGOs, consolidations with some tions were noted in the cavities. Initial baseline CT scan areas of interlobular septal thickening seen bilaterally. of patient was unavailable. Sputum culture of patient Multiple areas of cavitary changes were seen in bilateral revealed mucor growth. At the time of writing, he was in upper lobes and right middle lobe. Some of the cavities critical condition and on antifungals and antibiotics. showed irregular soft tissue density structures within, suggesting a fungal growth (Fig. 6). Sputum culture grew Case 4 candida albicans with amphotericin B, caspofungin, flu - A 74-year-old elderly male admitted to our hospital after conazole, flucytosine, micafungin sensitivity and voricon - recovering from COVID-19. He was a known diabetic azole resistivity. since 20  years. As the per the available information, he took the treatment from some other hospital includ- Discussion ing 8  mg injections of steroids twice a day. Initial base- As the COVID-19 pandemic continues, more specialists line scan was unavailable. HRCT thorax done in our are becoming aware of fungal co-infections. Aspergillus, hospital revealed large thick walled cavitary lesion with candida and mucor are the most common fungi detected internal septations and fluid level in the right lower lobe, so far. Most of the COVID-19 patients did not have a suspicious of invasive fungal aetiology. Patchy areas of sputum fungal evaluation at the start of their treatment. Dubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 4 of 10 Fig. 2 Axial HRCT scans showing imaging features of mucormycosis in case 2 of COVID-19. A–D CT axial images A and C show multiple cavitary lesions in the left upper and lower lobes. The repeat scans B and D show soft tissue attenuating growth (yellow arrows in B and D). Mild pneumomediastinum (red arrow in C) also noted. E, F A new cavity formed in the right upper lobe (green arrow in F) in pre-existing reverse halo sign (orange arrow in E). G, H Multiple soft tissue nodular opacities developed especially in left lower lobe in H in comparison with G D ubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 5 of 10 Fig. 3 Axial HRCT scans showing imaging features of Mucormycosis in Case 3 of COVID-19. CT axial images shows multiple cavitary lesions with irregular nodular growth and internal septations, in both lungs, look like arising from pre-existing reverse halo sign Also, detecting fungus with a single sputum fungal cul- time (~ 21  days), we suspected it to be a fungal lesion. ture is often difficult [10]. Thus, detection of fungal Rapid progression of GGOs into consolidation was also characteristics on HRCT thorax is a useful tool in this noted. Sputum culture confirmed mucor species. We pandemic, because of increasing incidence of superim- inferred that the rapidly progressing cavity with soft tis- posed fungal infection. sue attenuating growth within, along with surrounding Diabetes, glucocorticoids, hematopoietic malig- consolidation, was caused by superimposed mucor infec- nancy, persistent neutropenia, hematopoietic stem cell tion in this COVID patient. transplantation and trauma are all associated with an In patient 2, two HRCT scans were done at an inter- increased risk of mucormycosis in COVID-19 patients val of 9  days. Initial scan showed cavitary lesions with [11]. In our series, 5 out of 6 patients were diabetics and few smooth internal septations within. Subsequent scan all patients were on corticosteroid therapy due to COVID revealed new irregularly margined soft tissue attenuat- infection. ing growth along the walls within the cavity. A new cav- Imaging might be non-specific for the pulmonary ity was seen forming in anterior segment of right upper mucormycosis. Early imaging may show peri-bronchial lobe in the region of pre-existing reverse halo lesion. GGOs. Subsequently, the illness advances into consolida- Mucor species grew on sputum culture. Patient was a tion or nodules with a CT halo sign, followed by central known case of old pulmonary tuberculosis (PTB). Mucor necrosis and the creation of cavities [12]. The presence of can form cavities by itself and may show growth within, pleural effusion also favours mucor [13]. The reverse halo but in this case due to the absence of previous base line sign can help distinguish mucor from other fungal pneu- CT scan it was difficult to differentiate mucor from PTB. monias (like aspergillus) [14]. Case 1 in our presentation, Even if the cavity was pre-existing due to PTB the new in period of 21  days or less, had developed a large cavi- irregular soft tissue attenuating growth along the wall tary lesion with soft tissue attenuating growth along the and within the cavity was definitely suggestive of fungal margins of the cavity and this cavitary lesion was formed invasion. Moreover, newly formed cavity in pre-existing in the region where two patches of small reverse halo reverse halo sign favours fungal infestation. lesions were present in the first CT scan. Because of rapid Cases 3 and 4 were recovered COVID patients who progression of the small reverse halo lesions into a large were re-admitted due to worsening of symptoms. Both cavitation with surrounding consolidation within a short were diabetics. Baseline initial HRCT thorax was not Dubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 6 of 10 Fig. 4 Axial HRCT scans showing imaging features of Mucormycosis in Case 4 of COVID-19. 4 A, B CT axial image large cavitary lesions (yellow arrow in A) with thick internal septations, surrounded by thick consolidation. Dense consolidation also noted in left lower lobe (orange arrow in B). C Air fluid level within cavity (green arrow in C). D Minimal right pleural effusion (dark orange arrow in D) Fig. 5 Axial HRCT scans showing imaging features of Candidiasis in case 5 of COVID-19. A Axial HRCT thorax of case 5 shows small cavitary lesions with few internal septations and tiny soft tissue nodular opacities within (yellow arrow in A). Sputum culture revealed Candida species. B Bilateral pneumothorax can be seen (orange arrows in B) available. CT axial images in case 3 showed multiple walled cavitary lesion with internal septations and fluid cavitary lesions with irregular nodular growth and inter- level in case 4 strongly suggested fungal aetiology. Mini- nal septations, in both lungs, looks like arising from pre- mal right pleural effusion was favouring mucor proved existing reverse halo sign, favouring the fungal infection, on sputum culture. We infer that a repeat CT scan should came out to be mucor on sputum culture. Large thick be undertaken if already recovered COVID patients again D ubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 7 of 10 Fig. 6 Axial HRCT images of case 6 shows multiple cavitary lesions in both lungs with irregularly margined soft tissue attenuation nodular growth. Sputum culture revealed Candida species comes with progression or resurgence of symptoms and patients with pre-existing risk factors (diabetes and the presence of cavities on CT should be followed by fun- immunocompromised status), a repeat scan in 2–4 weeks gal related investigations. or earlier should be the norm. In severe COVID-19 patients with a broader spectrum It is very difficult to differentiate between differ - of antibacterial medications, parenteral diet and invasive ent invasive fungal species radiologically especially in examinations, or in patients with persistent neutropenia COVID scenario, as all of them show overlapping radi- and other immune disability causes, the risk of Candida ological features among themselves and with COVID. infection may increase dramatically [15]. In our 5th and However, presence of more than 10 nodules with pleu- 6th case, HRCT thorax revealed irregularly margined ral effusion and reverse halo sign is in favour of pulmo - cavitary lesions within the lungs pointing towards the nary mucormycosis rather than aspergillosis or other possibility of fungal infection. Sputum culture revealed fungal infections [13]. Pleural effusion was seen in case Candida species in both of these patients. 4 of mucormycosis and new cavities were formed in pre- After closely observing all the scans of these patients, existing reverse halo sign in cases 1, 2 and 3 of mucor- we infer that it is very difficult to differentiate the super - mycosis. The most common thin-section CT findings added fungal infection in COVID patients as GGOs, of pulmonary candidiasis are multiple bilateral nodular consolidation and reverse halo signs are commonly seen opacities often associated with areas of consolidation in both fungal and COVID infections. It becomes more [16]. Multiple cavitary lesions with surrounding consoli- difficult when there is diffuse involvement of lungs in dation may also be seen in pulmonary candidiasis [17]. COVID (deviating from the normal peripheral involve- This was correlating with our findings in cases 5 and 6 of ment) usually seen in severe patients. However, some candidiasis. We found that although invasive candidiasis clues that can suggest pulmonary fungal infestation showed cavities, yet their sizes were small and progres- are the presence of cavities with soft tissue attenuating sion was relatively slow. In our study, cases 1, 2, 3 and 4 irregular growth, pleural effusion and unusual rapid con - showed relatively rapid progression of cavities that could version of reverse halo to cavities and consolidation. In be attributed to highly invasive nature of mucor species. patients 1 and 2, new cavities evolved in the region where In general, pulmonary mucormycosis is rare in compari- there were reverse halo lesions in the previous scans; son with pulmonary aspergillosis and candidiasis, but in hence in the presence of reverse halo in severe COVID this COVID crisis, there is surge in mucor infections due Dubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 8 of 10 Fig. 7 Recommended protocol for triaging the COVID patients with suspicious pulmonary fungal infection to rampant steroid use and high prevalence of diabetes in and radiologically as these regions are also commonly countries like India. affected by fungal species. The most common fungal We suggest, in severe COVID patients (specially with pathogens associated with CNS infections include can- diabetes and immunosuppressive states), close monitor- dida and aspergillus species, and mucorales fungi [18]. ing and follow-up for the cavitary lesions with CT scan There seems to be a variety of factors that might lead should be undertaken. Appearance of new cavities or soft to fungal infections in these four COVID-19 patients: (1) tissue attenuating growth within existing cavity should mucormycosis is more likely to occur if diabetes is pre- be reported as probable fungal infection in this pan- sent. (2) Uncontrolled hyperglycaemia is frequently seen demic until proved otherwise and empirical antifungals as a result of corticosteroid use. Acidosis causes a low should be started as soon as possible because the super- pH, which is ideal for mucor spores to grow. (3) COVID- imposed fungal infection with COVID has significantly 19 frequently causes endothelialitis, endothelial damage, higher mortality. Once the diagnosis of pulmonary fun- lymphopenia, thrombosis and a decrease in CD4+ and gal infection is documented, other organs specially brain CD8+ levels, putting the patient at risk for opportun- and paranasal sinuses should be examined clinically istic fungal infection. (4) For mucormycosis, free iron D ubey et al. Egypt J Radiol Nucl Med (2022) 53:18 Page 9 of 10 is a great resource. Hyperglycaemia causes transferrin scanning in COVID hospitals will go a long way in saving and ferritin to be glycosylated, which lowers iron bind- patients. ing and allows for more free iron. Furthermore, a rise in cytokines, particularly interleukin-6, increases free iron Abbreviations via raising ferritin levels due to increased synthesis and HRCT : High-resolution computed tomography; RT-PCR: Reverse transcriptase reduced iron transport in COVID-19 patients. (5) In the polymerase chain reaction; GGO: Ground-glass opacities; CKD: Chronic kidney disease; CRP: C-reactive protein; ICU: Intensive care unit; PTB: Pulmonary setting of diminished WBC phagocytic activity, mucor tuberculosis. formation is encouraged by high glucose, low pH, and free iron [19]. Acknowledgements None. Pneumomediastinum and pneumothorax in cases 2 and 5, respectively, were without any iatrogenic cause, Authors’ contributions leading us to infer that this was a COVID-related compli- RD was involved in manuscript formation and analysis. KKS helped in manu- script analysis. SSM contributed to manuscript analysis. SP was involved in cation rather than a result of mechanical or barotrauma manuscript analysis. MG helped in data collection. SMM contributed to data [20, 21] The widespread alveolar damage to serious collection. All authors have read and approved the manuscript. COVID conditions might be one probable mechanism in Funding this case in which alveoli are prone to rupture [21]. None. Since HRCT thorax has become one of the most widely used diagnostic investigations in COVID Availability of data and materials The data were retrieved from our clinical and radiological database. patients, identifying radiological characteristics of fun- gal infection in COVID can thus be a valuable for tri- Declarations aging. In all of our cases, the radiological findings on HRCT thorax prompted the clinicians to rule out fun- Ethics approval and consent to participate gal infections. It was felt that a HRCT on admission and Ethical committee approval and consent has been taken for research purpose. discharge (10–14  days approximately) and a follow-up Consent for publication scan after 2 to 4  weeks (if the patient showed worsen- Appropriate written consent was taken from patient and/or relatives. ing of symptoms) for analysis by skilful radiologists will Competing interests be beneficial in picking up early fungal attack, if any, to The authors declare that they have no competing interests. pick up the effects of this deadly virus early, to avoid treatment delays and enhance the chances of survival. Received: 8 July 2021 Accepted: 30 December 2021 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. References A recommended protocol for detection of suspicious 1. 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Journal

Egyptian Journal of Radiology and Nuclear MedicineSpringer Journals

Published: Jan 6, 2022

Keywords: Pulmonary fungal infections; Mucormycosis; Invasive candidiasis

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