key: cord-1019782-0csnaanu authors: Gudiol, C.; Durà-Miralles, X.; Aguilar-Company, J.; Hernández-Jiménez, P.; Martínez-Cutillas, M.; Fernandez-Avilés, F.; Machado, M.; Vázquez, L.; Martín-Dávila, P.; de Castro, N.; Abdala, E.; Sorli, L.; Andermann, T.M.; Márquez-Gómez, I.; Morales, H.; Gabilán, F.; Ayaz, C.M.; Kayaaslan, B.; Aguilar-Guisado, M.; Herrera, F.; Royo-Cebrecos, C.; Peghin, M.; González-Rico, C.; Goikoetxea, J.; Salgueira, C.; Silva-Pinto, A.; Gutiérrez-Gutiérrez, B.; Cuellar, S.; Haidar, G.; Maluquer, C.; Marin, M.; Pallarès, N.; Carratalà, J. title: Co-infections and superinfections complicating COVID-19 in cancer patients: a multicenter, international study date: 2021-07-22 journal: J Infect DOI: 10.1016/j.jinf.2021.07.014 sha: 072805ca1e055c40e013aac1cf59f0786748044b doc_id: 1019782 cord_uid: 0csnaanu BACKGROUND: We aimed to describe the epidemiology, risk factors, and clinical outcomes of co-infections and superinfections in onco-hematological patients with COVID-19. METHODS: International, multicentre cohort study of cancer patients with COVID-19. All patients were included in the analysis of co-infections at diagnosis, while only patients admitted at least 48 hours were included in the analysis of superinfections. RESULTS: 684 patients were included (384 with solid tumors and 300 with hematological malignancies). Co-infections and superinfections were documented in 7.8% (54/684) and 19.1% (113/590) of patients, respectively. Lower respiratory tract infections were the most frequent infectious complications, most often caused by Streptococcus pneumoniae and Pseudomonas aeruginosa. Only seven patients developed opportunistic infections. Compared to patients without infectious complications, those with infections had worse outcomes, with high rates of acute respiratory distress syndrome, intensive care unit (ICU) admission, and case-fatality rates. Neutropenia, ICU admission and high levels of C-reactive protein (CRP) were independent risk factors for infections. CONCLUSIONS: Infectious complications in cancer patients with COVID-19 were lower than expected, affecting mainly neutropenic patients with high levels of CRP and/or ICU admission. The rate of opportunistic infections was unexpectedly low. The use of empiric antimicrobials in cancer patients with COVID-19 needs to be optimized. Bacterial and fungal infections represent a significant complication in some viral diseases, such as influenza [1] . Since the onset of the coronavirus disease 2019 (COVID- 19) pandemic, several studies have been published describing the epidemiology of infectious complications of COVID-19. Co-infections, diagnosed around the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, appear to be uncommon occurring in 0.6% to 3.2% of patients [2] [3] [4] [5] . Bacterial respiratory coinfections with Streptococcus pneumoniae or Staphylococcus aureus are the most 6 common causes of coinfections, whereas respiratory viral co-infections appear to be relatively rare [4, 6] . In contrast, nosocomial superinfections appear to be more frequent than coinfections, particularly among patients admitted to the intensive care unit (ICU) and those receiving high doses of corticosteroids [4, [6] [7] [8] [9] . These patients develop high rates of bloodstream infections and ventilator-associated pneumonia. Additionally, emerging data have demonstrated unexpectedly high rates of fungal infections, such as candidemia and invasive aspergillosis, particularly among mechanically ventilated patients [4, 5, [7] [8] [9] [10] . Infections due to multidrug-resistant (MDR) organisms have been reported some series [9] . Importantly, outcomes of patients with superinfections are likely to be poor, with prolonged hospital stay [6, 7, 9] and higher mortality [4, 6] . Onco-hematological patients, including hematopoietic stem cell transplant (HSCT) recipients are at a higher risk of acquiring COVID-19 [11, 12] , with the associated mortality reported to be higher than that in the general population [12, 13] . Yet, there is scarce information regarding infectious complications in cancer patients with COVID- 19 . Cancer as a comorbidity has been reported to be higher in patients with superinfections than in those without these complications [4, 9] . However, there are only two studies that mention very briefly the incidence and types of infectious complications. In a series of 536 patients with hematologic malignancies, of whom 82 were allogeneic HSCT recipients, the only information provided was that 187 patients (34.8%) presented additional infections [14] . In another series involving 77 HSCT recipients (37 allogeneic, 37 autologous, and five CAR T-cell recipients), ten patients developed infections (13%), caused by multiple organisms in some patients [15] . The infections reported were bloodstream infections (BSIs) (n=3), fungal pneumonia (n=3), 7 urinary tract infections (UTIs) (n=2), Clostridioides difficile colitis (n=2), bacterial pneumonia (n=1) and Epstein-Barr virus reactivation (n=1). Given these knowledge gaps, we designed an international multicenter cohort study of oncology patients with COVID-19. Our objectives were to define the epidemiology, risk factors and outcomes of infectious complications in these individuals, with a focus on co-infections present at the time of COVID-19 diagnosis and superinfections developing within 48 hours of admission. The COVICAN registry was an international, multicenter, combined prospective/retrospective, observational cohort study of adult patients with cancer and COVID-19, across 28 hospitals from 9 countries in Europe, North America and We collected data on demographics, comorbidities, cancer status and therapy, laboratory tests, microbiological results (cultures and non-culture diagnostics such as fungal biomarkers and viral PCR results), treatment, and outcomes. All testing and treatment was conducted as routine care by the individual centers. Co-infections or nosocomial superinfections were defined as infections occurring at COVID-19 diagnosis or after 48 hours of hospital admission for COVID-19, respectively. Neutropenia was defined as an absolute neutrophil count < 500 per mm 3 . Infectious were defined using the Centers for Disease Control National Healthcare and Safety Network [16] . A bloodstream infection (BSI) was defined as the growth of bacteria or fungi in at least one blood culture. BSIs caused by skin colonizers such as coagulase-negative staphylococci (CoNS) were considered to be significant when the pathogens grew in two or more blood cultures drawn from different sites. Catheterrelated BSIs were diagnosed in patients using at least one of the following criteria: (1) positive peripherally drawn blood cultures and positive blood cultures drawn from any of the catheter lumens; (2) time to positivity of at least 120 minutes for catheterdrawn blood cultures; or (3) positive culture of the same microorganism as that isolated from the catheter tip. Episodes of polymicrobial BSIs were those in which 9 more than one type of organism was isolated from one or more blood cultures within a 72-h period. Bacterial respiratory infections were diagnosed in patients with one or more positive cultures of respiratory pathogens obtained from the blood, pleural fluids, sputum, bronchoalveolar lavage, and tracheal aspirate and/or a positive urinary S. pneumoniae antigen test. Other respiratory pathogens such as influenza A and B viruses, respiratory syncytial virus, parainfluenza virus and metapneumovirus were also studied in respiratory samples, based on the requests of the attending physician. Aspergillus spp. tracheobronchitis was indicated by the isolation of Aspergillus species from respiratory samples of patients with purulent secretions and no radiological images. Invasive aspergillosis was diagnosed as possible, probable or proven according to EORCT/MSGERC criteria [17] . Descriptive statistics were used to determine characteristics of patients and infections. To compare the characteristics, risk factors and outcomes between infected and noninfected patients, the Mann-Whitney U Fisher test, chi-square and Fisher exact tests were used for categorical and continuous variables, as appropriate. Patients with and without co-infections were compared in a univariate analysis in order to identify potential risk factors for co-infection at COVID-19 diagnosis. Similarly, patients with and without superinfections were compared in a univariate analysis in order to identify potential risk factors for superinfections during hospitalization. Multivariate logistic regression analyses were performed to identify independent risk factors for coinfections and superinfections, using variables that achieved statistical significance in the univariate analysis. P-values < 0.05 were considered significant. A total of 684 patients were included, all of whom had data available about coinfections with COVID-19; 590 of these patients also had follow-up data for nosocomial superinfections. Three hundred patients had an underlying hematological malignancy; lymphoma (32.6%, 98/300) and multiple myeloma (20.6%, 62/300) were the most common conditions (Table 1) . Among the 384 patients with solid tumors, lung (22.1%, 85/384) and breast cancer (16.9%, 62384) were the most frequent malignancies (Table 1) . Overall, 7.8% (54/684) of patients presented with co-infections. The characteristics of patients with and without co-infections are shown in Table 1 . There were no relevant differences in the baseline characteristics of the patients. However, higher levels of Creactive protein (CRP) and the presence of neutropenia at diagnosis were more frequently reported in patients with co-infections. Antibiotic therapy was more frequently administered in this group of patients, particularly carbapenems (37.8% vs 19%, p=.006) and piperacillin-tazobactam (37.8% vs 23.1%, p=.044). Patients with coinfections were more likely to present worse outcomes, with higher rates of acute respiratory distress syndrome (56.9% vs 30.7%, p<.001) and a higher overall in-hospital case-fatality rate (53.8% vs 30.6%, p=.001). Table 2 details the types and etiologies of the 54 co-infections identified at COVID-19 diagnosis. All co-infections were bacterial. Respiratory tract infections were the most common (38.8%), followed by BSIs (33.3%). Streptococcus pneumoniae and Gramnegative bacilli (which included three cases of Pseudomonas aeruginosa) were the most common causes of respiratory tract infections (42.8% (9/21) and 33.3% (7/21), respectively). Eighty nine percent of S. pneumoniae pneumonias were diagnosed by urinary antigen test. Three episodes were associated with BSI (Haemophilus influenzae (n=2) and Escherichia coli (n=1)), and two episodes were polymicrobial. Among BSI episodes, catheter-related BSIs due to CoNS were the most common cause (33.3%, 6/18), followed by E. coli (27.7%, 5/18) and viridans group streptococci (VGS) (16.6%, 3/18). Three episodes of BSI were polymicrobial. Among the UTIs, E. coli was the most common pathogen (60%), and three episodes were polymicrobial. The risk factors for co-infections at COVID-19 diagnosis are also shown in Table 1 . By univariate analysis, higher levels of CRP and the presence of neutropenia at COVID-19 diagnosis were more frequently seen in patients with co-infections. In multivariate logistic regression, neutropenia was found to be the only significant independent risk factor for co-infections at COVID-19 diagnosis. Overall, 82 patients developed 113 superinfections during hospitalization (19.1%). In our large multinational cohort of onco-hematological patients with COVID-19, we found that the rate of co-infections at the time of diagnosis was more than double the rate reported in the general population [2] [3] [4] [5] but the rate of superinfections was comparable to those observed in previous reports in the general population [6] [7] [8] [9] . Neutropenia was a major risk factor for both co-infections and superinfections, whereas ICU admission was also a risk factor for superinfections. Surprisingly, no respiratory viral co-infections were encountered, and the rate of opportunistic infections, particularly IPA, was unexpectedly low. Nevertheless, patients with coinfections and/or superinfections presented worse outcomes, with higher case fatality rates. Taken together, our data highlight the need for improved diagnostics to identify patients at highest risk for infections following COVID-19, in order to prioritize these patients for antimicrobial therapy. Although there are some published studies involving large cohorts of oncohematological patients with COVID-19, data on the rates, characteristics and outcomes of infectious complications in this population are lacking [14, 15, [18] [19] [20] [21] . This is of special concern since cancer patients are at a higher risk of acquiring COVID-19 [11, 12] . Due to their often severely impaired immune system, it has been widely assumed that the risk of developing additional infectious complications is high. As a consequence, it has been reported that the number of antimicrobial prescriptions in cancer patients with COVID-19 has been high [18] [19] [20] [21] , even in patients showing no evidence of infectious complications during hospitalization, which reached 81.5% in our study. This is of special concern in the current era of emerging antimicrobial resistance, since a 14 reduction of antibiotic consumption is a cornerstone in the fight against the development of resistance. In our series, co-infections mainly occurred in patients with neutropenia and high levels of CRP. These included both bacterial co-infections commonly encountered in cancer patients (S. pneumoniae, P. aeruginosa), as well as BSIs, which are common in cancer patients due to the presence of indwelling catheters, mucositis, and neutropenia [22, 23] . These findings suggest that antibiotics may not need to be administered to all cancer patients who present with COVID-19, but may instead be targeted more to those with neutropenia and elevated CRP levels. No other respiratory viruses were identified, although this may have been a result of limited diagnostic testing in 2020, due to swab and PCR reagent shortages. Nearly 20% of patients developed nosocomial superinfections, which was lower than we had originally expected, as many patients had previously received immunosuppressive therapies and/or immunomodulatory treatments for COVID-19. reported in the literature vary greatly, ranging from 0.1% to 47.4% [24] [25] [26] [27] [28] . We hypothesize that these findings may be explained by the challenges encountered in diagnosing CAPA: diagnostic criteria are poorly-defined, the radiological findings are often non-specific in individuals with concurrent COVID-19 pneumonia, testing may be infrequently sent due to lack of clinician awareness, the performance of fungal biomarkers assays in CAPA is unknown (although the galactomannan assay is expected to have a good performance in neutropenia), and it is difficult to distinguish colonization from infection. Nonetheless, the rate of IPA observed in patients with COVID-19, even when they carry a baseline immunosuppressive condition (such as our patients), appears to be much lower than that observed in patients with influenza [12] [13] . Other invasive fungal infections, such as Candida, were not observed in our cohort compared to other reports [29] [30] . The in-hospital case-fatality rate in our cohort was 32.4% (215/664), which is significantly higher than that reported for the general population, but in line with several other reports involving cancer patients [18] [19] [20] [21] . Patients with infectious complications in our study had worse outcomes, higher rates of acute respiratory distress syndrome, ICU admission, and increased mortality. These findings are consistent with those of previous reports of oncology patients with respiratory viral infections [4, 6, 7, 9] . However, there are several variables that may influence the outcomes of cancer patients with COVID-19, particularly the presence of uncontrolled underlying malignancy. Thus, these worse outcomes cannot be entirely attributed to the development of infectious complications. 16 Limitations of the study include its partial retrospective design and the fact that diagnostic testing was performed according to the discretion of the individual sites. Our rate of infection may be falsely low, particularly in the setting of enhance COVID-19 transmission-based precautions limiting the ability of clinicians to perform diagnostic tests for infection. Additionally, systematic testing for viral co-infections was not performed by all participating centers. Despite these limitations, ours is the first published report addressing infectious complications in immunocompromised cancer patients with COVID-19. We include data for a large number of patients from 28 centers located in nine countries around the world, thereby improving the generalizability of our results. In conclusion, in our large multinational cohort of cancer patients with COVID-19, co-infections were higher than in the general population, mainly affected neutropenic patients and critically ill ICU patients, and were associated with severe disease and poor outcomes. Further studies are needed to define the risk factors for bacterial and fungal infections in oncology patients with COVID-19 to better optimize antimicrobial use in these vulnerable individuals, and avoid unnecessary antibiotic exposure. The authors declare no conflicts of interest. from pleural effusion. f Three episodes were polymicrobial: E. coli + viridans group streptococci (n = 1), E. coli + Enterococcus faecium (n = 1), and Pseudomonas aeruginosa + Staphylococcus aureus (n = 1). g Three episodes were polymicrobial: Klebsiella oxytoca + E. faecium (n = 1), E. coli + E. faecalis (n = 1), and P. aeruginosa + Proteus mirabilis (n = 1). h One episode was associated with bacteremia. aeruginosa + Aspergillus fumigatus (n = 1), and Staphylococcus aureus + Enterobacter aerogenes (n = 1). c Four episodes were polymicrobial: Enterococcus faecium + P. aeruginosa (n = 1), Enterococcus faecalis + Candida parapsilosis (n = 2), and E. faecalis + Staphylococcus haemolyticus (n = 1). d Two episodes were polymicrobial: E. faecium + P. aeruginosa (n = 1), and E. faecalis + P. aeruginosa (n = 1). e This episode was bacteremic. f This was an episode of candidemia. g One episode was caused by E. coli + Candida tropicalis. 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COVID-19-Associated Pulmonary Aspergillosis COVID-19-Associated Invasive Aspergillosis: Data from the UK National Mycology Reference Laboratory Incidence and mortality of COVID-19-associated pulmonary aspergillosis: A systematic review and meta-analysis Critically ill patients with COVID-19 and candidaemia: We must keep this in mind Candidemia in COVID-19 patients: incidence and characteristics in a prospective cohort compared to historical non-COVID-19 controls Chronic obstructive pulmonary disease; Broadspectrum cephalosporins: cefepime, ceftazidime, ceftolozane-tazobactam and ceftazidime-avibactam Antifungal therapy (more than one antifungal was administered in some patients): fluconazole (n=5), voriconazole (n=3), micafungin (n=3), caspofungin (n=2), anidulafungin (n=2) posaconazole (n=1), Amfotericin B (n=1) Inflammatory biomarkers (median, IQR) C-reactive protein (mg/L) Procalcitonin (g/L) We thank the ESCMID Study Group for Immunocompromised Hosts (ESGICH) for supporting the study. We also thank the Centres de Recerca de Catalunya (CERCA) Programme and the Generalitat de Catalunya for institutional support.Funding statement 17 This study was supported by the Spanish Plan Nacional