key: cord-0702433-1s0bqnuy authors: Pemán, Javier; Ruiz-Gaitán, Alba; García-Vidal, Carolina; Salavert, Miguel; Ramírez, Paula; Puchades, Francesc; García-Hita, Marta; Alastruey-Izquierdo, Ana; Quindós, Guillermo title: Fungal co-infection in COVID-19 patients: should we be concerned? date: 2020-09-14 journal: Rev Iberoam Micol DOI: 10.1016/j.riam.2020.07.001 sha: 4bf30317df11b8e0ee9fde2be88d0ebe6731ecfc doc_id: 702433 cord_uid: 1s0bqnuy Critically ill COVID-19 patients have higher pro-inflammatory (IL-1, IL-2, IL-6, tumor necrosis alpha) and anti-inflammatory (IL-4, IL-10) cytokine levels, less CD4 interferon-gamma expression, and fewer CD4 and CD8 cells. This severe clinical situation increases the risk of serious fungal infections, such as invasive pulmonary aspergillosis, invasive candidiasis or Pneumocystis jirovecii pneumonia. However, few studies have investigated fungal coinfections in this population. We describe an update on published reports on fungal coinfections and our personal experience in three Spanish hospitals. We can conclude that despite the serious disease caused by SARS-CoV-2 in many patients, the scarcity of invasive mycoses is probably due to the few bronchoscopies and necropsies performed in these patients because of the high risk in aerosol generation. However, the presence of fungal markers in clinically relevant specimens, with the exception of bronchopulmonary colonization by Candida, should make it advisable to early implement antifungal therapy. Los pacientes gravemente enfermos con COVID-19 presentan concentraciones más elevadas de citoquinas pro-inflamatorias (IL-1, IL-2, IL-6, factor de necrosis tumoral alfa) y anti-inflamatorias (IL-4, IL-10), menor expresión de interferón-gama y un número más bajo de células CD4 y CD8. Esta grave situación clínica aumenta el riesgo de padecer coinfecciones fúngicas, como la aspergilosis pulmonar invasora, la candidiasis invasora o la neumonía por Pneumocystis jirovecii. Sin embargo, pocos estudios han investigado las coinfecciones fúngicas en esta población. En esta revisión, describimos una actualización de las publicaciones sobre coinfecciones fúngicas en esta población de pacientes y nuestra experiencia personal en tres hospitales españoles. Podemos concluir que a pesar de la grave enfermedad causada por el SARS-CoV-2 en muchos pacientes, la baja frecuencia de micosis invasoras se debe probablemente a las pocas broncoscopias y necropsias realizadas en estos pacientes debido al alto riesgo de producción de aerosoles. Sin embargo, la presencia de marcadores fúngicos en muestras clínicas relevantes, con la excepción de la colonización broncopulmonar por Candida, debería aconsejar la instauración precoz de una terapia antifúngica. To date, very few studies have been specifically designed to investigate superinfections by bacteria, fungi or other viruses in COVID-19 patients 1, 16 . In addition, limited data on superinfections are included in published studies. The scarce information on co-infections in these patients may be because most studies are retrospective, with poor quality data, and do not include protocols for additional microbiological studies 14, 20 . Furthermore, in most health institutions routine diagnostic procedures, such as bronchoscopies, induced sputum collection, necropsy, and microbiological tests, have been cut down to avoid staff exposure to SARS-CoV-2 12 . About 5-30% of COVID-19 patients become critically ill and require intensive care unit (ICU) admission 44 18 . As it is well known, ICU patients, especially those undergoing mechanical ventilation, are at greater risk to develop bacterial or fungal infections. Severe COVID-19 is associated with immune dysregulation, affecting both T-helper cell 2 (Th2) and Th1 responses, including the cytokine release syndrome, which contribute to lung pathology and promote pulmonary microbial proliferation and a subsequent infection 29 . Critically ill COVID-19 patients have higher pro-inflammatory (IL-1, IL-2, IL-6, tumor necrosis alpha) and anti-inflammatory (IL-4, IL-10) cytokine levels, less CD4 interferon-gamma expression, and fewer CD4 and CD8 cells 9,37 . This severe clinical situation increases the risk of invasive fungal infections (IFI), such as invasive pulmonary aspergillosis (IPA), invasive candidiasis (IC) or Pneumocystis jirovecii pneumonia (PJP). The issue that patients with COVID-19 might be at risk of suffering a CAPA is an increasing medical concern. Although IPA is a well-known complication in immunocompromised patients, half of the cases occur in patients who are often non-neutropenic when admitted to ICU 33 . In these patients, severe influenza is a recognized risk factor for developing IPA, and several studies from Asia and Europe have reported up to 28% of IPA in patients with severe influenza 19, 39 . However, these high incidence rates of influenza-associated pulmonary aspergillosis (IAPA) may not be universal, because in a North American study only 7% of the patients suffered IPA 35 . Respiratory epithelium disruption, along with dysfunctional mucociliary clearance and local immune impairment, are important pathophysiological factors in the development of IAPA 33 . Most IPA cases affect people without immunodeficiency, so the European Organization for Research and Treatment of Cancer Mycoses Study Group (EORTC-MSG) criteria 13 to define invasive aspergillosis cannot be applied. Therefore, it is suggested to apply the AspICU algorithm described by Blot et al. 8 Table 1 , died in the first ten days after the diagnosis of CAPA. Available information on CAPA in Asian patients is more imprecise, as published reports do not adequately differentiate between bacterial and fungal co-infection due to lack of appropriate mycological studies. For instance, in China and other countries GM testing is rarely available 11, 46 . Thus, in a cohort of 221 ICU patients with COVID-19 in Wuhan, China, mycoses were diagnosed in seven individuals, but causative pathogens were not identified 45 (Table 1) . Despite the fact that Schauwvlieghe et al. 33 reported that serum GM was positive in 65% of patients with IAPA, only 6 out of 30 patients with CAPA (20%) from the studies collected in the Table 1 were serum GM positive. However, 17 out of 28 patients (61%) were BAL GM positive (Table 1) . Nevertheless, only a restricted role for bronchoscopy has been recommended in COVID-19, because it is an aerosol-generating procedure that poses risks to patients and personnel. Bronchoscopy is recommended only when the intervention is considered lifesaving. In addition to Aspergillus spp., severely ill COVID-19 patients are exposed to other fungal pathogens such as Candida species and P. jirovecii. All the classic risk factors for developing candidemia in a critically ill patient are present in COVID-19 patients admitted to the ICU: mechanical ventilation, parenteral nutrition, broad-spectrum anti-bacterial treatment, indwelling central venous or bladder catheters, older age, comorbidities, lymphopenia, corticosteroids, etc. In critically ill patients or in patients at COVID-19 advanced stages, to all these well-known risk factors must be added the use of tocilizumab, an IL-6 receptor monoclonal albicans and attributed to line-related infections 20 . The authors found no difference in the incidence rate of candidemia when contrasting the COVID-19 cohort to a control group of 216 influenza positive patients admitted during 2019/2020 flu season. In our experience, candidemia crude mortality rate is lower (12%) than in other at risk groups of patients (Table 2) . Different species of Candida have also been isolated from respiratory specimens (TA, BAS and BAL) from COVID-19 patients as unique pathogen and considered as cause of co-infections 10, 25 ( Table 2) To date, although we have observed cases of PJP (unpublished), only one episode of co-infection by P. jirovecii has been reported in a patient with COVID-19 and ARDS 28 . In this patient, the high level of BDG detected in serum (305 pg/ml) prompted to additional testing for P. jirovecii with a qualitative real-time PCR assay from a tracheal aspirate, which was positive. It is noteworthy that this patient had neither a known underlying immunodeficiency nor any other classical risk factor for PJP, such as malignancy, organ transplantation, or prolonged exposure to systemic corticosteroids. This case also highlights the potential utility of serum BDG for diagnosing PJP in COVID-19 patients, which is particularly relevant given concerns about healthcare transmission associated with performing bronchoscopy in these patients. Besides the fungal pathogens above mentioned, the high aggressive feature of the SARS-CoV-2 virus to the lung tissue and the large bilateral alveolo-interstitial lesions make the occurrence of other IFI very likely. There is a special concern for those IFI with a primary pulmonary entry and an airborne route transmission, such as mucormycosis and cryptococcosis. In endemic countries and in those with high mobility of travelers from or to these countries, the diagnosis of histoplasmosis should also be considered. 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