Case Report: Diagnostic challenge of COVID-19 associated pulmonary aspergillosis (CAPA) [version 1; peer review: 1 approved with reservations]

Background: Coronavirus disease 2019 (COVID-19) was declared a pandemic in March 2020 by the World Health Organization (WHO). Severe COVID-19 is represented with acute respiratory distress syndrome (ARDS) that requires mechanical ventilation. Moreover, recent studies are reporting invasive fungal infection associated with severe COVID-19. It is unclear whether the prescription of immunotherapies such as corticosteroids, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection itself is risk factor for COVID-19-associated invasive pulmonary aspergillosis (CAPA). Hence, fungal infections present an additional uncertainty in managing COVID-19 patients and further compromise the outcome. Case study: Here we report a case of SARS-CoV-2 complicated by invasive pulmonary aspergillosis (IPA) in a patient with no traditional risk factors for IPA. Admitted to ICU due to ARDS on mechanical ventilation, the patient deteriorated clinically with unexplained increased of fraction of inspired oxygen (FiO2) requirement from 50% to 80%. Investigations showed borderline serum galactomannan, nonspecific radiological findings reported to be atypical for COVID-19, and the respiratory sample grew Aspergillus spp. Main diagnosis: COVID-19 related fungal infection. The patient was treated with antifungal therapy for four weeks. He improved clinically after one week of starting antimicrobial treatment. After a prolonged ICU stay (87 days) due to infection control precaution, he was discharged from the ICU and moved to a long-term facility for further management and support. Conclusions: This case highlights the diagnostic challenge in such cases. and the importance of early recognition of CAPA which can optimize therapy by administration of appropriate antifungal agents that may impact mortality. Open Peer Review


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Background
Invasive pulmonary aspergillosis (IPA) is typically thought to cause disease in immunocompromised hosts, particularly in neutropenic patients. In the last two decades, it has been more commonly recognized in critically ill patients, particularly those with severe acute respiratory distress syndrome (ARDS) 1   The patient was started on continuous renal replacement therapy (CRRT); his clinical status deteriorated with increased ventilation requirement of FiO 2 50% to 80%, PEEP 8 to 16 cm H 2 O on day 4. A chest X-ray showed multiple bilateral ill-defined patchy opacities in the right lower lung zone ( Figure 1). A computed tomography (CT) scan for his chest was done and showed multiple bilateral patchy ground-glass opacities ( Figure 2, Figure 3). Bilateral lower lobe consolidations with air bronchogram showed greater involvement of the right lower lobe, while an unenhanced CT of the brain demonstrated hyperdense foci seen in the left inferior frontal, right parietal lobes with surrounding edema, and right central sulcus compatible with intra-parenchymal hemorrhage and subarachnoid hemorrhage, respectively. A follow-up MRI of the brain was obtained, showing an increased gyral pattern of T1 and FLAIR sequence, as observed in the bilateral occipital, bilateral frontal, and  right parietal lobes, likely related to laminar necrosis from the anoxic-ischemic event. Gradient recalled echo (GRE) sequence showed scattered areas of blooming artifacts that are likely to be related to recent extensive hemorrhage. The brain findings were suggestive of hemorrhage and hypoxic injuries of vascular causes of previous cardiac arrest events.
On day 0, the patient was started on hydroxychloroquine 400mg orally every 12 hours for 1 day, followed by a maintenance dose of 200mg every 12 hours and azithromycin 500mg orally once followed by a maintenance dose of 250mg daily, respectively, for a total duration for 5 days. His antimicrobial therapy was escalated to Meropenem 0.5 gm IV every 12 hours. He continued to worsen, and thus his septic screen was repeated. His blood and urine culture remained negative.
Tracheal aspirate culture on day 0 grew Aspergillus fumigatus and Aspergillus flavus ( Figure 4a, Figure 4b, Figure 5a, Figure 5b). Bronchoscopy was considered; however, it was not done due to concerns of COVID-19 transmission to the house staff. The patient was then started on dual antifungal therapy (day 4) for 1 week; Voriconazole 400mg orally every 12 hours as a loading dose, then 200mg every 12 hours as maintenance.
In addition, the patient was given Caspofungin 70mg IV as a loading dose, followed by 50mg daily. After this Voriconazole monotherapy therapy (200mg orally every 12 hours) for a total duration of four weeks was completed in the hospital. One week after starting antifungal therapy (day 10 in the ICU), the secretions improved and the ventilator setting was decreased to FiO 2 30%. Unfortunately, the patient on day 5 of ICU admission was found to be in a vegetative state secondary to anoxic brain damage post-cardiac arrest. The Glasgow Coma Scale was GCS 10/15 on tracheostomy.
The patient had a prolonged ICU stay due to infection control precaution; his stay was complicated with rhabdomyolysis, difficulty to wean him from ventilation, nosocomial infection    after 30 days of ICU admission, and persistent COVID-19 virus shedding up to 73 days. The patient was then moved to a long-term facility (on day 87) after discharging him from the ICU.

Discussion
This case further supports the association between IPA and severe COVID-19 infection. It highlights the importance of early diagnosis and treatment of this serious complication that can impose increased mortality. The diagnosis of IPA in patients in ICU without classical risk factors like neutropenia remains challenging [1][2][3][4][5][6][7][8][9] .
Multiple studies from China have reported different rates of Aspergillus infections among patients with COVID-19. The estimated rates of Aspergillus co-infection in these combined studies are as follows: in Jiangsu province, 60/257 (23.3%), Zhejiang province, 8/104 (7.7%); and lastly, Wuhan, 13/48 (27%). All these reported CAPA cases lack standardization in diagnostic criteria and use specific definitions to identify and define CAPA 10,11 . A European case series reported severe COVID-19 pneumonia complicated by IPA. All 27 cases were for patients admitted to the ICU, the majority of whom were intubated. The median duration between CAPA diagnosis and symptom onset was six days. Aspergillosis diagnosis was as early as three days post ICU admission or as late as 28 days 10 .
Of the 27 patients, 12 (44%) received corticosteroids during their ICU stay, and 19 (70%) were treated with mould-active antifungal medication [5][6][7][8] . Bartoletti   non-neutropenic patients in ICUs. Lastly, repeated chest imaging to assess clinical response of the patient with IPA after completion of antifungal therapy unfortunately was not done, as the patient was kept on conservative and minimal intervention management.

Conclusions
IPA can complicate severe COVID-19 pneumonia. The diagnosis of CAPA is often challenging and requires a high index of suspicion. A constellation of clinical, biochemical, microbiological, and radiological criteria needs to be incorporated to establish the diagnosis. Timely diagnosis and management are required for better outcomes.

Data availability
All data underlying the results are available as part of the article and no additional source data are required.

Consent
Written informed consent for publication of their clinical details and clinical images was obtained from the relative of the patient.