key: cord-1038610-u0m3mtv2
authors: Trovato, Laura; Calvo, Maddalena; Migliorisi, Giuseppe; Astuto, Marinella; Oliveri, Francesco; Oliveri, Salvatore
title: Fatal VAP-related pulmonary aspergillosis by Aspergillus niger in a positive COVID-19 patient
date: 2021-02-18
journal: Respir Med Case Rep
DOI: 10.1016/j.rmcr.2021.101367
sha: 8bf119f1d68caeb60916e911bfb0a1f3a9fcb97b
doc_id: 1038610
cord_uid: u0m3mtv2

Invasive pulmonary aspergillosis, known as a complication in patients with severe respiratory syndromes, recently showed a correlation with COVID-19 pneumonia, and the clinical characteristics of COVID-19 associated pulmonary aspergillosis (CAPA) have been described. Unfortunately, infections by the Aspergillus genus are often diagnosed in post-mortem time, because of diagnostic delays and a rapid worsening of respiratory conditions. Literature data document, in fact, only few cases of COVID-19 Aspergillus niger coinfection. The aim of this study was to describe a case of a VAP-related probable pulmonary aspergillosis by Aspergillus niger in a COVID-19 patient. Despite the definition of fungal etiology and the rapid administration of antifungal therapy, the patient died while on ventilator support because of severe respiratory impairment.

IPA, caused by the Aspergillus genus, is known as a common complication in patients with severe respiratory syndromes and is also related to high mortality rates [1, 2] . There are many predisposing factors to the development of IPA, basically recognized in prolonged treatment with corticosteroids and lung epithelial damage [1] . Several cases of IPA have been documented as super-infections in patients with severe respiratory illness such as influenza and MERS-CoV [1, 3] . Starting in December 2019 many severe respiratory syndrome cases caused by Coronavirus-19 (SARS-CoV-2) have been diagnosed. The clinical impact of this infection defines a highly dysregulated immune response and diffuse lung damage, which lead to the early onset of secondary infections [2, 3] . Here we describe a case of invasive pulmonary aspergillosis by Aspergillus niger in a patient with COVID-19 pneumonia and acute respiratory distress syndrome.

J o u r n a l P r e -p r o o f

In October 2020, a 73-year-old man was admitted to the accident and emergency department of the University Hospital of Catania, Sicily, Italy, reporting fever, cough and diarrhea. Vital signs were recorded as the following: blood pressure of 160/87 mmHg, heart rate of 85 beats per minute, respiratory rate of 40 beats per minute and SPo2 of 78%. A chest X-ray showed bilateral infiltrates ( Figure 1 ) and a nasopharyngeal swab sample was collected and tested positive for COVID-19 using molecular testing. The patient was moved to the ICU with the diagnosis of Coronavirus-19 pneumonia. Clinical history was updated to include a previous diagnosis of diabetes and hypertension.

Corticosteroid therapy with dexamethasone (12 mg/day) and C-PAP ventilation were immediately required. In the following days, laboratory tests showed significant increases of white blood cells (up to 30210/mm3) and lactate (up to 864 U/L), and low albumin (down to 2.27 g/dL). There was also a high increase of C-reactive protein up to 101.87 mg/L. On day 4, seric levels of the GM (Platelia Aspergillus; Biorad) and 1,3-β-D-glucan (Fungitell;

Associates of Cape Cod Inc., Falmouth, Massachusetts, USA) were prescribed because of the patient's risk factors, which tested negative. On day 10 ventilator support with oro-tracheal intubation was implemented, due to a rapid decline of the patient's consciousness and respiratory quality. Because of a fever episode, antibiotic treatment with meropenem (3g/day) was started and a peripheral blood sample was taken for a microbiological culture, J o u r n a l P r e -p r o o f which tested negative. On the same day some surveillance exams were performed: cultures from rectal, nasal and pharyngeal swabs reported a normal microbiota, while a culture from a urinary sample revealed 100000 ufc/ml of Pseudomonas aeruginosa. Because of this positive result the urinary catheter was removed and a therapeutic lavage with antibiotics was carried out, with complete resolution. On day 16 a new chest X-ray was performed that showed a pulmonary worsening (Figure 2 ). [4] . Some literature reports evaluated the effectiveness of isavuconazole against the Aspergillus genus and the reliability of the MIC strip method for its susceptibility test [5, 6] . According to these reports, the susceptibility test for isavuconazole was performed using the MIC strip method and showed a MIC value of 2 mg/L. The patient was put on voriconazole 800 mg/day. On day 19, the patient died in the ICU of heart failure, while he was still on ventilator support.

According to recent literature data (June 2020), about 38 cases of COVID-19 associated pulmonary aspergillosis are known [1, 2] . Percentages are probably underestimated owing to a diagnostic delay or to the lack of clinical recognition [1] . Most COVID-related pulmonary aspergillosis cases are, in fact, belatedly diagnosed, often in post-mortem time. In our case, because of the patient's critical issues, it was not possible to collect samples from the lower respiratory tract regularly. This inconvenience had a negative impact on the possibility to define a fungal colonization by Aspergillus and on the timeliness of a correct diagnosis of pulmonary aspergillosis. These delays, together with patient's risk factors represented by extensive lung damage and prolonged treatment with corticosteroids [3] , involved a rapid worsening of the respiratory condition. The patient also reported a previous diagnosis of diabetes, which is related to structural modifications of blood vessels and predisposes to fungal angioinvasion. To clarify the eventuality of a previous chronic Aspergillus colonization, a detection of Aspergillus-specific antibodies by agar gel immunodiffusion was performed on serum. The negative result leads us to the assumption that the patient, most likely, was infected in a hospital setting during intubation. According to recent data Aspergillus sp. are recognized as a potential cause of VAP in immunocompetent hosts [7, 8] .

Unfortunately, fungi are often not included among the possible causes of VAP in non-immunocompromised patients with other risk factors and therefore Aspergillus shows its angioinvasive properties for a long period before the real diagnosis of pulmonary aspergillosis [8] . Assuming that the infection of our patient was a VAP-related pulmonary aspergillosis, a frequent check of seric and colonization parameters would have allowed a prompter diagnosis: in the six days between oro-tracheal intubation and diagnosis of pulmonary aspergillosis, we do not have regular reporting of a mycological surveillance for this patient. This omission led to a dangerous consequence: Aspergillus had sufficient time to proliferate and to angioinvade the patient's respiratory tract, therefore the diagnosis and the administration of voriconazole were not enough, also considering the critical status of the pulmonary epithelium. Notwithstanding his critical clinical condition, the patient contrasted the progression of the infection for a brief time, both because of the absence of a marked neutropenia, which is often a predisposing condition to pulmonary aspergillosis and because of the involvement of Aspergillus niger, whose virulent nature is widely confirmed but it is lower when compared to other Aspergillus species. In fact, although Aspergillus niger is able to produce a severe pulmonary disease it is rarely reported as a cause of invasive aspergillosis, while it is often described as the etiological agent of otomycosis and cutaneous J o u r n a l P r e -p r o o f infections [9] . Moreover, in a study that investigated the presence of triazole-resistant Aspergillus isolates in agricultural areas in Southern Italy, the presence of other Aspergillus species was reported. These species, although less pathogenic than A. fumigatus, are very frequently isolated in Sicily and can represent a potential cause of invasive disease in patients at risk [10] . Despite the definition of fungal etiology and the rapid administration of voriconazole, the patient died because of the severe impairment of his respiratory condition.

Consequently, invasive pulmonary aspergillosis should be investigated as a possible complication in cases of severe respiratory syndromes, even in immunocompetent hosts [11, 12] . A rapid diagnosis can lead to the development of an accurate therapeutic plan and 

COVID-19 Associated Invasive Pulmonary Aspergillosis: Diagnostic and Therapeutic Challenges

COVID-19 Associated Pulmonary Aspergillosis (CAPA)-From Immunology to Treatment

COVID-19 associated pulmonary aspergillosis

Reference method for broth dilution antifungal susceptibility testing of filamentous fungi: approved standard

Evaluation of MIC Strip Isavuconazole Test for Susceptibility Testing of Wild-Type and Non-Wild-Type Aspergillus fumigatus Isolates

Evaluation of isavuconazole MIC strips for susceptibility testing of Aspergillus and Scedosporium species

Ventilator-associated pneumonia

Invasive Pulmonary Aspergillosis in Ventilator-associated Pneumonia: The Hidden Enemy?

Aspergillus niger: an unusual cause of invasive pulmonary aspergillosis

Environmental Isolates of Multi-Azole-Resistant Aspergillus spp. in Southern Italy

Pulmonary aspergillosis in critically ill patients with Coronavirus Disease 2019 (COVID-19)

Fatal aspergillosis complicating severe SARS-CoV-2 infection: A case report

We wish to thank the Scientific Bureau of the University of Catania for language support.