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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 9  |  Issue : 2  |  Page : 306-309

COVID-19 associated pulmonary aspergillosis- A case report


Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra, India

Date of Submission05-Oct-2021
Date of Decision24-Oct-2021
Date of Acceptance26-Oct-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Dr. Vishal Mangal
Department of Medicine, India-Tajikistan Friendship Hospital, Qurgonteppa, Bokhtar- 735140
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_226_21

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  Abstract 


Coronavirus disease-19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2. Viral illnesses such as influenza and COVID-19 are known to coexist with fungal infections, including Aspergillosis. The cases of COVID-19-associated pulmonary Aspergillosis (CAPA) have been reported in the recent past; however, there is a paucity of literature from India. Hence, we report a case of CAPA in a 55-year-old diabetic male from India who was successfully managed with anti-fungals and had a favorable outcome. This case highlights the importance of the high index of suspicion for CAPA in patients with severe COVID-19 pneumonia and acute respiratory distress syndrome who fail to improve or deteriorate clinically and radiologically despite standard therapy. The diagnosis must be confirmed with galactomannan assay from serum or bronchoalveolar lavage samples – early diagnosis and prompt management with anti-fungal results in a favorable outcome.

Keywords: Aspergillus, coronavirus disease-19, pulmonary, tocilizumab


How to cite this article:
Kumar A, Kumar S, Mangal V, Menon AS. COVID-19 associated pulmonary aspergillosis- A case report. Arch Med Health Sci 2021;9:306-9

How to cite this URL:
Kumar A, Kumar S, Mangal V, Menon AS. COVID-19 associated pulmonary aspergillosis- A case report. Arch Med Health Sci [serial online] 2021 [cited 2022 Jan 24];9:306-9. Available from: https://www.amhsjournal.org/text.asp?2021/9/2/306/334011




  Introduction Top


Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), is the worst pandemic the world has seen in recent times.[1] COVID-19 is known to have co-infection with several bacterial, viral, and rarely fungal infections. With glucocorticoids being the standard of care in the management of COVID-19, there is a significant rise in the fungal infection incidence; however, data from India are lacking.[2],[3] The common fungal infections associated with COVID-19 are Candida, Cryptococcus, Mucorales, and Aspergillus spp. The term “Aspergillosis” describes the illness caused by allergy, lung invasion, cutaneous infection, and the extrapulmonary dissemination caused by Aspergillus species like Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, and Aspergillus terreus. Recently, the incidence of invasive pulmonary Aspergillosis with COVID-19, also known as COVID-19-associated pulmonary Aspergillosis (CAPA), is increasing with the use of interleukin-6 receptor antagonist, namely Tocilizumab. CAPA is associated with high morbidity, with a reported mortality rate of 52%.[4] Early diagnosis and management of CAPA may have a favorable outcome. The data on CAPA are limited to individual case reports and case series. Hence, we report a case of CAPA in 55-year-old diabetic male from India who was successfully managed with anti-fungal therapy and had a favorable outcome.


  Case Report Top


A 55-year-old male with a history of diabetes mellitus for 10 years on oral antidiabetic drugs with poor glycemic control became symptomatic with moderate grade fever, dry cough, and progressively worsening dyspnea of 3 days duration. He tested positive by reverse transcriptase-polymerase chain reaction for SARS CoV-2 on day three of the illness. On day five of his illness, he was admitted with further worsening dyspnea from modified medical research council Grade II to IV. On physical examination, he had a pulse rate of 110 beats/min regular in rhythm, respiratory rate of 28/min, blood pressure of 172/96 mm of Hg, and hypoxia with the saturation of 84% on room air improving to 94% on Oxygen @ 12 L/min by rebreather mask. On initial investigation, the patient had mild thrombocytopenia, elevated aspartate aminotransferase, alanine aminotransferase, blood urea, and hyponatremia with raised inflammatory markers [Table 1]. Initial arterial blood gas analysis was diagnostic of Type I respiratory failure [Table 1], and a chest radiograph was suggestive of bilateral nonhomogeneous opacities in the peripheral zones of both lung fields [Figure 1]a. He was managed as an severe COVID-19 pneumonia with acute respiratory distress syndrome with parenteral steroids, anticoagulants, empirical antibiotics, intravenous Remdesevir (for five days), antihypertensives, and basal-bolus insulin as per the institutional protocol.
Table 1: Laboratory parameters of the patient during the hospital stay

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Figure 1: Chest radiograph anteroposterior view. (a) At the time of admission, showing peripheral nonhomogenous opacities in bilateral lower zones Left > Right. (b) Post Injection Tocilizumab, showing nonhomogenous opacity in the left middle and lower zone. Also less marked shadowing in right middle and lower zones. (c) At the time of discharge, reticulonodular opacities in bilateral middle and lower zones, with elevation of the right hemidiaphragm possibly collapse or effusion or pleural thickening

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His general condition remained static during the initial 14 days. Subsequently, he developed a headache, slight agitation with increased oxygen requirement. On urgent evaluation, his inflammatory markers were markedly elevated with uncontrolled hyperglycemia with no evidence of ketoacidosis [Table 1]. Because of likely features of cytokine release syndrome and no evidence of sepsis, he was administered two doses of Interleukin-6 receptor Antagonist, Tocilizumab (400 mg intravenous) on day 15 and day 17 of the illness, and antibiotics were upgraded. post Tocilizumab, he still had an increasing oxygen requirement requiring high flow nasal cannula on 50 L/min on day 19 of the illness. A repeat chest radiograph showed a new nonhomogeneous opacity in the left middle zone [Figure 1]b. Because of the constant immunesuppressed state, CAPA was suspected. The CAPA diagnosis was made based on clinical deterioration, new opacities on chest radiograph and raised serial serum Galactomannan (GM) levels 3.27 and 6.5. He was started on Caspofungin 70 mg iv on day one, followed by 50 mg iv daily for the next 2 weeks, followed by voriconazole 200 mg twice a day orally. His oxygen requirement started decreasing from the 26th day of the illness with marginal improvement in the chest radiograph on follow-up [Figure 1]c. After 5 weeks of admission, he was discharged on domiciliary oxygen therapy and antifibrotic therapy (Pirfenidone 400 mg three times a day orally). Subsequent follow-up on the telephone revealed that the patient required domiciliary oxygen at home for 6 weeks, and after that, he did not require oxygen. Informed written consent was obtained from the patient before the publication of this manuscript.


  Discussion Top


Fungal infections associated with COVID-19 reported recently include Candida, Aspergillus, and Mucor more frequently than others. The incidence of CAPA is reported to be 3% to 33%.[5],[6] The incidence was 5% among the largest case series by Permpalung N et al., from the United States of America.[7] Among the 15 CAPA case series in the intensive care unit patients, 158 CAPA cases out of the 1702 COVID-19 patients occurred, and only four cases of CAPA had a definite diagnosis, while the majority had a probable or putative diagnosis.[8] Various reports have highlighted that the CAPA patients survived even without anti-fungal therapy.[6],[9] These observations might imply that in some critically ill COVID-19 patients, positive Aspergillus tests reflect colonization rather than invasive disease. Hence, the evidence of aspergillus in clinical specimens should be interpreted with caution on only those patients with clinical deterioration or new opacities on chest imaging.

The definitions of invasive fungal infections such as proven invasive fungal disease, probable invasive fungal disease, and endemic mycosis given by the European Organization for Research and Treatment of Cancer (EORTC)/Mycosis Study Group Education and Research Consortium (MSGERC) cannot be used in the context of CAPA because EORTC/MSGERC definitions apply to specific host criteria such as neutropenic patients, recipients of allogeneic stem cell transplant, inherited immunodeficiencies, and prolonged glucocorticoid use.[8] CAPA should be suspected in a COVID-19 patient on mechanical ventilation for more than 5 days, receiving a high dose of long-term glucocorticoids in case of clinical deterioration with no other explanation or the presence of new-onset cavitary or nodular opacities on chest imaging. Our patient had clinical deterioration in the 3rd week of admission while on glucocorticoid therapy. Moreover, he had new-onset opacities on the chest radiograph; however, he was never on mechanical ventilation.

The diagnosis of CAPA as per the task force report on the diagnosis and clinical management of CAPA[8] requires bronchoscopy and bronchoalveolar lavage (BAL) with any one of the following tests positive: (1) Demonstration of fungal hyphae on BAL specimen, (2) BAL GM positivity, (3) demonstration of Aspergillus by the polymerase chain reaction, (4) demonstration of Aspergillus by culture, and (5) positive serum GM. The serum GM is generally negative; however, it increases the probability of CAPA if positive along with BAL GM. Positive serum GM is associated with poor outcomes. Our patient had clinical deterioration, and after ruling out the other possible causes such as pneumothorax, secondary bacterial infection, pulmonary thromboembolism, we considered the diagnosis of CAPA. We established the diagnosis of CAPA based on fresh radiological opacities and positive serum GM.

IL-6 levels are raised and have a protective role in Aspergillosis.[10] Hence, the use of Tocilizumab in COVID-19 patients can predispose them to CAPA.[11] As in our case, the patient had persistently high IL-6 levels in the 3rd week of the illness, and clinical and radiological deterioration post Tocilizumab made us suspect CAPA.

Voriconazole, Caspofungin, and liposomal Amphotericin B alone or in combination are the most commonly used anti-fungals to treat invasive Aspergillosis. Our patient was successfully treated with anti-fungal Caspofungin, followed by Voriconazole.

Patients with diabetes and immunocompromised state are associated with CAPA, as in our case and review by Lai and Yu.[12] The case-fatality rate reported among the largest series of 34 cases of CAPA was 64.7%, which is very high. It becomes more important to highlight the importance of early clinical suspicion, early diagnosis, and effective management of IPA, especially in the 3rd week of the illness if a patient of COVID-19 is worsening or not improving persistently.

This case had a few weaknesses, like this patient was managed at the dedicated COVID-19 hospital with limited infrastructure. We did not have the facility of bronchoscopy and BAL. The fungal cultures were not available, and the only imaging done was a chest radiograph. However, the clinical worsening, the new opacities on chest radiograph, and the favorable outcome following the anti-fungal therapy add to the fact that the patient had CAPA.


  Conclusion Top


In this COVID-19 pandemic, more and more cases of associated fungal infections are being diagnosed. The present case report highlights the importance that CAPA must be suspected in the patients with severe COVID-19 pneumonia and acute respiratory distress syndrome in the 3rd week of the illness with persistently raised IL-6 levels and worsening clinical status. They should undergo bronchoscopy, and fungal hyphae should be demonstrated in the BAL specimen or culture. GM assay can be used on BAL specimens or in serum which can provide an additional clue to the diagnosis. Early diagnosis and management with anti-fungal, namely Caspofungin and Voriconazole, may have a favorable outcome.

Informed consent

Informed written consent was obtained from the patient for the publication of this article.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

The Government of India sponsored all the medicines used. The authors received no financial support for the authorship and/or publication of this article.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
WHO Director-General's Opening Remarks at the Media Briefing on COVID-19 – 08 June, 2020. Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19-8-june-2020. [Last accessed on 2020 Jan 12].  Back to cited text no. 1
    
2.
Koehler P, Cornely OA, Böttiger BW, Dusse F, Eichenauer DA, Fuchs F, et al. COVID-19 associated pulmonary aspergillosis. Mycoses 2020;63:528-34.  Back to cited text no. 2
    
3.
van Arkel AL, Rijpstra TA, Belderbos HN, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19-associated pulmonary aspergillosis. Am J Respir Crit Care Med 2020;202:132-5.  Back to cited text no. 3
    
4.
Salmanton-García J, Sprute R, Stemler J, Bartoletti M, Dupont D, Valerio M, et al. COVID-19-associated pulmonary aspergillosis, March-August 2020. Emerg Infect Dis 2021;27:1077-86.  Back to cited text no. 4
    
5.
Sarrazyn C, Dhaese S, Demey B, Vandecasteele S, Reynders M, Van Praet JT. Incidence, risk factors, timing, and outcome of influenza versus COVID-19-associated putative invasive aspergillosis. Infect Control Hosp Epidemiol 2021;42:1149-50.  Back to cited text no. 5
    
6.
Alanio A, Dellière S, Fodil S, Bretagne S, Mégarbane B. Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19. Lancet Respir Med 2020;8:e48-9.  Back to cited text no. 6
    
7.
Permpalung N, Chiang TP, Massie AB, Zhang SX, Avery RK, Nematollahi S, et al. COVID-19 associated pulmonary aspergillosis in mechanically ventilated patients. Clin Infect Dis 2021;223:1–9. doi: 10.1093/cid/ciab223.  Back to cited text no. 7
    
8.
Verweij PE, Brüggemann RJ, Azoulay E, Bassetti M, Blot S, Buil JB, et al. Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis. Intensive Care Med 2021;47:819-34.  Back to cited text no. 8
    
9.
Bartoletti M, Pascale R, Cricca M, Rinaldi M, Maccaro A, Bussini L, et al. Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: A prospective study. [published online ahead of print July 28, 2020]. Clin Infect Dis. doi: 10.1093/cid/ciaa1065.  Back to cited text no. 9
    
10.
Su H, Li C, Wang Y, Li Y, Dong L, Li L, et al. Kinetic host defense of the mice infected with Aspergillus fumigatus. Future Microbiol 2019;14:705-16.  Back to cited text no. 10
    
11.
Cai S, Sun W, Li M, Dong L. A complex COVID-19 case with rheumatoid arthritis treated with tocilizumab. Clin Rheumatol 2020;39:2797-802.  Back to cited text no. 11
    
12.
Lai CC, Yu WL. COVID-19 associated with pulmonary aspergillosis: A literature review. J Microbiol Immunol Infect. 2021;54(1):46-53. doi: 10.1016/j.jmii.2020.09.004.  Back to cited text no. 12
    


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