key: cord-0824916-bd0k78b2
authors: Busca, Alessandro; Marchesi, Francesco; Cattaneo, Chiara; Trecarichi, Enrico Maria; Delia, Mario; Del Principe, Maria Ilaria; Candoni, Anna; Pagano, Livio
title: When Viruses Meet Fungi: Tackling the Enemies in Hematology
date: 2022-02-13
journal: J Fungi (Basel)
DOI: 10.3390/jof8020184
sha: 8f616b25490c48800a95aa8cf865887dceba50b2
doc_id: 824916
cord_uid: bd0k78b2

The association of invasive fungal infections (IFI) and viral infections has been described in patients with hematologic malignancies (HM), in particular in hematopoietic stem cell transplant recipients. Regrettably, the diagnosis is often challenging, making the treatment inappropriate in some circumstances. The present review takes into consideration the viral infections commonly associated with IFI. Clinical presentation of IFI and viral infections, risk factors, and impact on the outcome of HM patients are discussed throughout the paper.

Opportunistic infections represent a major hindrance to the successful outcome of patients receiving high-dose chemotherapy and stem cell transplantation for the treatment of hematologic malignancies (HMs). There is an extensive knowledge of invasive fungal infections (IFI) and viral infections as single complications in hematologic patients, while the relationship between these two entities is still far from being investigated in detail. The association of IFI and virus is not completely unexpected: the two infectious complications share common risk factors, such as high-dose chemotherapy, prolonged neutropenia, and lymphopenia, the presence of graft-versus-host disease (GVHD), and related treatments including high-dose steroids [1, 2] . Several viral infections have been reported to be associated with an increased incidence of IFI; for instance, cytomegalovirus (CMV), community-acquired respiratory virus, and, more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [3] [4] [5] [6] [7] [8] .

The present review aims to evaluate the currently available literature on the relationship between viral infections and IFI in patients affected by HMs.

CMV reactivation or, less frequently, primary infection is a typical complication occurring in immunocompromised patients, such as HMs. This complication has been extensively studied and is extremely relevant in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) [9] . On the contrary, outside allo-HSCT setting, the incidence of CMV reactivation was historically considered low, but the recent extensive use of pleiotropic immunosuppressive treatments and novel targeted agents in lymphoproliferative diseases led to a consideration of this viral complication as clinically relevant even in non-transplanted hematologic malignancy (HM) patients [10] .

In allo-HSCT settings, CMV reactivation is often associated with end-organ disease (CMV disease) resulting in pneumonia in most cases and, more rarely, in a gastro-intestinal, hepatic, retinal, or central nervous system disease. At the present, the incidence of CMV disease is only 2-3% based on randomized clinical trials [11] [12] [13] [14] [15] and ranges between 5% and 10% in real-life practice [16, 17] . Donor source (haploidentical and cord blood transplant), use of post-transplant high-dose cyclophosphamide, GVHD, and CMV serological status of patients and donors strongly influence the risk of post-transplant CMV reactivation and disease. CMV-related mortality significantly decreased over the last years, due to the introduction of pre-emptive treatment [9] and Letermovir prophylaxis [15] .

CMV reactivation in HM patients treated with high-dose chemotherapy, immunosuppressive drugs, or novel targeted agents, is less frequent with a variable rate of CMV reactivation, ranging between 2% and 41% [18] [19] [20] [21] [22] [23] [24] [25] [26] . Overall, high-dose steroids, advanced disease status, poor performance status, and treatment with Rituximab, Alemtuzumab, Bortezomib, Fludarabine, and Idelalisib were the main risk factors for CMV reactivation in these clinical settings. In most cases, CMV reactivation in HM patients outside the allo-HSCT setting is easily manageable and CMV end-organ disease is a rare complication.

Several studies have so far been published about CMV and IFI in HMs, most of them focusing on patients undergoing allo-HSCT. Table 1 shows the most relevant published studies addressing this issue on adult HMs in the last 20 years. Many studies focusing on allo-HSCT setting suggested that CMV infection was an independent risk factor for IFI. However, the results showed in these studies were quite heterogeneous and not fully comparable, being obtained in retrospective study cohorts, having different methodological designs, and evaluating variously the CMV outcome. In particular, the association between IFI and CMV end-organ disease was evaluated in only four studies [27] [28] [29] [30] . In all these studies a CMV end-organ disease was an independent risk factor for IFI: transplanted HM patients were exposed to a 3-7-fold higher risk of developing an early or late IFI. In the remaining nine studies, the authors focused on CMV DNAemia or antigenemia. In seven out of these nine studies [31] [32] [33] [34] [35] [36] , a significant association between CMV viremia and early or late IFI occurrence was found, whereas the remaining two [37, 38] failed to demonstrate a significant association. Of note, the only prospective cohort study among all those analyzed, published by Atalla and coworkers, showed that CMV reactivation was a significant risk factor for the late occurrence of invasive mold infections (hazard ratio: 5.5), together with a diagnosis of lymphoma and prolonged neutropenia [32] . Outside allo-HSCT, there are fewer published studies. In a recent study about patients suffering from lymphoproliferative malignancies undergoing autologous hematopoietic stem cell transplantation (ASCT), Marchesi et al., showed a strong correlation between CMV symptomatic infection and early occurrence of IFI. However, a cause-effect relationship was not demonstrated in this study [3] . Moreover, Stanzani et al., reported a significant relationship at univariable but not at multivariable analysis between CMV and invasive mold infections in a large retrospective study on 1695 hospitalized HM patients [39] . The proper mechanisms leading to the increase of IFI in patients affected by CMV reactivation/end-organ disease are far from being well characterized and understood. Putative mechanisms may be neutropenia induced by anti-CMV treatments (i.e., ganciclovir), but also the immunosuppressive effect of CMV itself, sustained by the impairment of macrophages migration and antigen presentation [40] . As expected, the most frequently reported fungal infections were those caused by Aspergillus species, particularly invasive pulmonary aspergillosis (IPA). The reason for this lies of course in the higher incidence of IPA among HM patients compared to other fungal infections; however, some studies have suggested that the local viral inflammation in the pulmonary tract may lead to IPA occurrence [29, 41] . CMV disease was an independent risk factor for invasive aspergillosis together with steroid treatment and occurrence of lower respiratory tract infection 

The impact on clinical outcome of both CMV infection and IFI has been largely studied and well-characterized in HM patients when considered as single entities. However, the specific impact of concomitant CMV reactivation/end-organ disease and IFI remains to be determined. In allo-HSCT setting, Yong et al., showed a significant impact of IFI on overall survival irrespective of the presence of a GVHD; on the contrary, no survival differences occurred if patients did or did not experience CMV reactivation, with the only exception of those in which an acute GVHD was diagnosed [4] . However, in this study, no data about the clinical impact of concomitant CMV reactivation/disease and IFI were reported. In a retrospective study on allo-HSCT setting published in 2014, Gimenez et al. reported slightly significant higher mortality in patients with concomitant active CMV infection and invasive aspergillosis (IA) compared with patients affected only by IA [39] . Moreover, some other data showed a negative impact of pulmonary CMV co-infection in patients with Pneumocystis jirovecii pneumonia (PJP) [42] . To the best of our knowledge, there are still no specific published data on this issue in HMs outside the allo-HSCT setting. Further studies are warranted to better establish the real impact of CMV-IFI co-infection on morbidity and mortality of HM patients in both allo-HSCT and outside allo-HSCT setting.

Among hematologic patients, allogeneic HSCT recipients are at high risk for CMV-IFI co-infection -CMV infection emerged in several studies as an independent risk factor for the occurrence of IFI. -Neutropenia induced by CMV treatments, and the immunosuppression related to CMV infection itself may be considered as the main factors underpinning the IFI co-infection

Influenza (A and B) viruses are single-stranded enveloped RNA viruses belonging to the Orthomyxoviridae family. The Influenza A virus subtype is the most common human pathogen with two major antigens on the viral capsid surface: the hemagglutinin (subtypes H1 to H18) and the neuraminidase (subtypes N1 to N11), of which minor or major genetic variations in the corresponding RNA genome occur each year. Influenza B virus is less prone to antigenic variation. The Influenza virus is transmitted from person to person via the respiratory route (with small-particle aerosols generated by infected humans) spreading across the population during the fall-to-winter and winter-to-spring months (the "so-called" flu season). Worldwide, 3-5 million people (2% to 10% of the global population) develop a severe influenza infection every year, leading to 50,000-100,000 deaths annually in Europe and USA and, of the hospitalized patients, 5-10% needs ICU admission [43, 44] . The most severe and problematic influenza complication is the lower respiratory tract infection (LRTI), with localized or diffuse pneumonia. The incidence of influenza infection in patients with HM and allo-HSCT recipients has been reported between 1,3 and 40% according to the hematologic patient population and the laboratory diagnostic methods [45] . In HMs, progression from upper to LRTI occurs after a median of 1 week of infection onset, and recent studies suggest that approximately 30% of influenza infections in patients with leukemia and allo-HSCT recipients are complicated by concomitant influenza pneumonia. In addition, some studies have highlighted an association between the degree of lymphopenia and the development of influenza-related pneumonia, particularly in allo-HSCT patients [44] .

Bacterial super-infection, mainly with Streptococcus pneumoniae and Staphylococcus aureus, is a well-known complication of severe influenza and influenza-related pneumonia. However, in recent years, an increasing number of publications on influenza-associated IFI are reported, mainly IPA (Influenza-Associated Pulmonary Aspergillosis-IAPA), particularly in patients with influenza A infection [43, 44, 46, 47] . In these cases, the most frequently associated underlying conditions were immunosuppressive therapy for a variety of underlying diseases or procedures (including allo-HSCT), HM, and diabetes [43] . A recent study of the Dutch-Belgian Mycoses Study Group (DB-MSG) evaluated the incidence of IAPA in a large cohort of 432 patients (of whom 117 were immunocompromised) admitted to the ICU with severe influenza. In this study, a total of 83 of the 432 patients (19%) were diagnosed with IAPA, and the 90-day mortality was 51%, which was higher than the mortality in the 349 patients without IAPA (28%; p < 0.001) [48] . In addition, the multivariate analysis showed that the emergence of IAPA was independently associated with 90-day mortality, as were age, APACHE II score, diabetes, and immunocompromised status according to EORTC/MSG criteria [48] . Other similar epidemiological studies confirmed, in Europe and Asia, an incidence of IAPA ranging between 12% to 28% in patients with severe influenza and influenza-related pneumonia with a very high related mortality [48, 49] .

The diagnosis of IAPA is frequently performed early after ICU admission (5-7 days after admission) based on results of fungal culture from sputum or tracheal aspirates and/or on Galactomannan antigen (GM) detection in serum and, preferentially, in bronchoalveolar lavage (BAL) [50] . A diagnostic bronchoscopy is recommended to collect BAL, to look for tracheobronchitis, and to biopsy evident lesions. If IAPA is excluded on admission, but progressive radiological and/or clinical deterioration is observed during or after ICU admission, a repeated radiological and/or bronchoscopy evaluation is needed to exclude IAPA again.

To decrease the risk of progression to LRTI, an early recognition and treatment of influenza infection is crucial in HM, particularly in allo-HSCT recipients. In this patient population, antiviral treatment should be started as early as possible. Neuraminidase inhibitors (NAIs) are the first-line agents for the treatment of influenza A or influenza B. The currently available NAIs include oral oseltamivir, inhaled zanamivir, and very recently intravenous peramivir. The standard dose of oseltamivir for treatment of influenza is 75 mg twice daily for 5 days. In the cases with IAPA is indicated to treat these patients, according to guidelines for the treatment of IPA, with voriconazole (current gold standard therapy for IPA according to ECIL/ESCMID-ECMM-ERS/IDSA guidelines) [43, 44] or liposomal amphotericin B. Other interventions, including nebulized antifungal therapy in cases with invasive Aspergillus tracheobronchitis, can also be considered to achieve the best therapeutic antifungal drug concentrations at the site of infection.

In clinical practice, influenza vaccination of HMs is strongly recommended by international guidelines as the primary method of influenza, and severe related complications, prevention (including IAPA). Patients with HM are reported to have low immunogenicity of influenza vaccine, particularly those who receive SCT and drugs such as rituximab, which depletes memory B cells [51] . Although the immune response to vaccination could be partial, vaccination remains the backbone of prevention of influenza infection and its complications (including IAPA) in HM patients [43, 44] .

-Influenza infection is a cause of significant morbidity and mortality in patients with HM, particularly those undergoing chemotherapy and recipients of allo-HSCT. -Close monitoring for the development of IAPA and bacterial pneumonia is very important in managing hematologic patients with influenza -A prompt antiviral therapy is associated with reduced morbidity and mortality attributable to influenza in patients receiving chemotherapy or allo-HSCT -Influenza vaccination remains the most crucial prevention strategy, even if efficacy may be limited in immunocompromised hosts.

Respiratory virus infections (RVIs) include a large number of viruses-namely, Parainfluenza (PIV), Respiratory Syncytial Virus (RSV), Adenovirus (AdV), Human Metapneumovirus (HMPV), Human bocavirus (HBoV), Coronaviruses (CoVs) other than SARS-CoV-2, and Rhinovirus (HRV). RVIs are increasingly reported as a cause of significant morbidity and mortality in recipients of allo-HSCT and patients with HM [52, 53] . Based on the widespread use of molecular diagnostics, the epidemiology and spectrum of clinical manifestations of these infections might be better characterized, thus deciphering the RVIs other than influenza in terms of incidence and clinical outcomes. Furthermore, the possible association between fungi and RVIs remains an expected data, although largely misunderstood.

Because of the broad range of diagnostic strategies (i.e., multiplex polymerase chain reaction (PCR), viral culture, direct antigen fluorescence), as well as the defined seasonality of RVIs, the incidence varies from 1 up to 10, 20, 30, 40, and 50% for HPMV, CoV, PIV+ Adenovirus and RSV, respectively. Of note, the mortality rate is by no means negligible [45] . In particular, the detection of RVIs in the immediate pre-transplant period is associated with LRTI and a decreased survival at 100 days, in particular in symptomatic patients [54, 55] . Progression from URTI to LRTI is associated with an increased likelihood of fatal outcomes [54] [55] [56] [57] . Consequently, attention should be paid to the factors correlating with the development of LRTI; for instance, older age, lymphopenia, early post-transplant infection, myeloablative conditioning regimen, HSCT from mismatched donors, and GVHD necessitating high-dose immunosuppressive agents [52, 56, 58] . In addition, risk factors for increased mortality are mismatched allogeneic HSCT, high-dose steroids at the time of LRTI, oxygen requirement, and mechanical ventilation [54, 57, [59] [60] [61] [62] .

RVI seems to be an important risk factor for the development of IA in allo-HSCT, although it is difficult to define the contribution of viral infection among the large spectrum of conditions favoring immunosuppression [29] . It has been postulated that RVIs in the early posttransplant period make the lungs a target for allo-immunity thus contributing to the development of idiopathic pneumonia syndrome, bronchiolitis obliterans syndrome, and bronchiolitis obliterans organizing pneumonia [63] . As a result, coinfection with other viruses and superinfection with bacteria or fungi are described in allo-HSCT recipients with RVI [54, 57, [63] [64] [65] [66] [67] . In particular, Hardak et al. [66] reported that allo-HSCT and GVHD were predictors of polymicrobial infections: 8 pulmonary IA episodes out of 27 (30%) RVIs were documented with BAL. In a series of hematological and immunosuppressed patients who were investigated with BAL for suspected PJP, the coinfection was documented in 2 out of 5 (40%) Pneumocystis documented infections. [67] Ajmal et al., reported 4 cases of coinfections in immunocompromised patients, although 2 out of these cases were possible IFI [68] . Interestingly, in a series of 54 post-RVI IPA infections (including 14 cases of influenza), the coinfection was demonstrated to occur early, even within one week after the diagnosis of RVIs [46] .

Clinical symptoms vary according to the spectrum of illness ranging from paucisymptomatic to respiratory failure, in URTI and LRTI, respectively. Regarding imaging investiga-tions, it is often difficult to distinguish between RVIs and other infectious and/or noninfectious entities. Imaging may vary from diffuse bilateral ground-glass infiltrates, small multifocal nodules, bronchial vascular thickening, and/or airspace consolidation [69] [70] [71] [72] . Regrettably, it should be emphasized that roughly half of the immunocompromised patients have a radiographic abnormality at the time of diagnosis but there are no features able to discriminate coinfections (RVIs + IPA) from IPA alone [46] . Only a retrospective study of CT findings in HCT recipients found that those infected with RSV were more likely to have an airway-centric pattern of disease with tree-in-bud opacities and bronchial wall thickening with or without consolidation. Adenovirus appeared as multifocal consolidation or ground-glass opacities without inflammatory airway findings [73] , although these features are suggestive, rather than highly specific.

The outcome of patients with RVI and IFI remains particularly dismal, especially in allo-HSCT recipients where the coinfection is mostly reported ( Table 2 ). 

-Scattering data on IFI associated with RVI have been reported in the literature. -Allo-HSCT recipients represent the subjects with the highest risk of coinfection with fungi and RVIs -

The diagnosis may be demanding due to a lack of specific radiologic features.

General Population IFI has been described as severe complications of the clinical course in patients with Coronavirus disease , in particular in ICU settings. The wide use of broadspectrum antibiotics, corticosteroids and/or immunomodulatory drugs, and central venous catheters have been hypothesized as the main risk factors for IFI in COVID-19 patients; besides these, comorbidities (e.g., chronic lung diseases, diabetes mellitus) and the direct pulmonary damage caused by SARS-CoV-2 have been reported as favoring factors [74] [75] [76] [77] .

Invasive yeast infections have been described in patients with COVID-19 infection, with candidiasis by far the most frequently reported infection, albeit with a high variability of incidence rates ranging from 0.7 to 23.5% [75, 78] . Although a role of SARS-CoV-2 has been hypothesized in favoring invasive candidiasis during COVID-19, directly by a cellular injury or indirectly by immunological dysregulation, a clear association between these two infectious diseases has not been demonstrated to date [75, 78] .

Invasive mold infections have been described as associated or at high incidence in COVID-19 patients [78] . Singh et al., have recently reviewed 101 reported cases of mucormycosis in non-HM patients with active COVID-19 or post-COVID-19 course [79] . Most of these cases suffered from diabetes mellitus (80%) and had received corticosteroids (76.3%); the infection involved mainly nose and sinuses (88.9%), but also rhino-orbital localization was frequently reported (56.7%); interestingly, 81% of these cases were reported in India, thus indicating an important role of local epidemiology in the pathogenesis of the disease; the overall mortality was 30.7% [79] .

Moreover, IPA is reported to have a high incidence in patients with severe COVID-19 and treated in ICU. Mitaka et al., recently conducted a systematic review and meta-analysis including 28 observational studies (conducted mainly in Europe) with a total of 3148 ICU patients diagnosed with COVID-19 to estimate incidence and mortality of COVID-19associated pulmonary aspergillosis (CAPA); they reported an estimated incidence of CAPA in the ICU of 10.2% (range 2.3-34.4%); however, CAPA was associated with a mortality rate as high as 54.9% (range 22.2-94.4%) [77] .

Several factors have been highlighted as predisposing to CAPA. These include the severe lung damage due to COVID-19 course, the use of corticosteroids (and/or immunomodulators) in patients with respiratory failure and mainly in those with acute respiratory distress syndrome (ARDS), the large use of broad-spectrum antibiotics, the presence of pulmonary chronic underlying diseases, and immunological alterations during COVID-19, such as leukopenia or lymphopenia and immune dysregulated response [75, 76] .

The mechanisms underlying the pathogenesis of CAPA have not been exactly understood, with only a few hypotheses. Firstly, corticosteroids could reduce the production of pro-inflammatory cytokines involved in an immune response against Aspergillus spp., mainly by suppressing the production of Nuclear Factor-kB (NF-kB), and on the other hand, increase the production of other cytokines (e.g., IL-10) which are responsible for inhibition of phagocytosis of the fungus [80] . Secondly, a possible role of molecules released by damaged pulmonary cells during COVID-19, i.e., danger-associated molecular patterns (DAMPs), which could display a signaling endogenous activity responsible for a dysregulated immune response leading to a higher risk for fungal infections in general, and CAPA in particular [75] . Thirdly, a direct role of SARS-CoV-2 by up-regulation of IL-1 pathway has been hypothesized on promoting CAPA [74] . Finally, to date, it is not clear if the immunomodulators (in particular, IL-6 antagonists) currently indicated in the treatment of patients suffering from COVID-19 and with ARDS could promote CAPA onset [74] .

Diagnosis and management of CAPA present peculiar aspects concerning IPA in immunocompromised patients-in particular, those suffering from HMs; instead, clinical and prognostic characteristics of CAPA seem to be more similar to influenza-associated pulmonary aspergillosis (IAPA). IAPA and CAPA share the following characteristics: high prevalence, mainly in ICU settings, absence of classic risk factors for invasive mold infections (e.g., severe immunosuppression), presence of lymphopenia, and lack of classic radiological findings. In this regard, it should be underscored that there is large heterogeneity in diagnostic clinical (e.g., specific case definitions or diagnostic algorithms, such as EORTC/MSG definitions, AspICU algorithm) [8] and microbiological criteria (e.g., a cut-off of galactomannan index on serum or bronchoalveolar lavage) used among the studies reporting cases of CAPA and published to this date, as reported in the systematic review and meta-analysis of Mitaka et al. [77] . Importantly, this heterogeneity could have caused important biases in estimated prevalence and mortality rates reported. To provide specific criteria for CAPA diagnosis and recommendations for its management, a consensus statement was drafted by experts and endorsed by the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) [8] . Two different algorithms for the diagnosis of proven, probable, or possible pulmonary and tracheobronchial forms of CAPA have been purposed, including histological, microbiological, clinical, and radiological criteria. Voriconazole and isavuconazole have been recommended as first-line drugs for CAPA treatment; however, since multi-triazole resistance in Aspergillus spp. complicating cases of critical COVID-19 pneumonia have been reported, susceptibility tests for antifungal drugs (in particular for azoles), as well as therapeutic drug monitoring are recommended [81, 82] .

Patients with HM have always been considered at risk for fungal infections, due to the known immunosuppression both for the underlying diseases and for the specific treatments. It is known that fungal infections can worsen the prognosis of HMs. Indeed, adverse outcomes have been reported also in COVID-19 HMs, with related mortality higher than 30% [82] [83] [84] [85] [86] [87] [88] . However, epidemiologic data concerning COVID-19 HMs often lack information about possible co-infections. Only a few studies report data about co-infections or secondary infections in COVID-19 HMs, with findings often elusive. Among these, Sanchez-Pina et al. [89] reported a series of 39 patients, with no cases of bacterial or fungal co-infections, while Wu et al. [90] reported a not otherwise specified mixed co-infections in 8 out of 14 COVID-19 hematologic patients. In the Italian cohort study [91] , no specified additional infections occurred in 187/536 (35%) COVID-19 hematologic cancer patients.

Therefore, specific information about fungal co-infections, mainly aspergillosis, in HM patients often refers to case reports or small series [91] [92] [93] [94] [95] [96] [97] [98] , which show the highly unfavorable prognosis of fungal co-infection also in most of this subset of patients. Only two cases of mucormysosis in HM COVID-19 patients have been reported, as the main risk factors for concurrent mucormycosis in COVID-19 patients seem to be diabetes mellitus and chronic renal failure [99] . Table 3 summarizes single cases of COVID-19 hematologic cancer patients with fungal co-infections. Very recently, a multicenter cohort study of cancer patients with COVID-19 describing the epidemiology, risk factors, and clinical outcomes of co-infections and super-infections has been published [100] . In this large series, hematologic patients represent 43.8% of all cancer patients enrolled. Although co-infection at diagnosis and nosocomial super-infection were documented in 7.8% and 19.1% of patients, only one case of invasive pulmonary aspergillosis and two cases of polymicrobial bacteremia including Candida spp. were documented. Three cases of Aspergillus spp. tracheobronchitis were also documented. Reasons for this low incidence may be the retrospective nature of the study, the fact that diagnostic tests were performed according to the discretion of the physicians, and the lower sensitivity of biomarker tests in non-neutropenic patients. Regardless, fungal co-infections have been reported to significantly increase the risk of death in COVID-19 hematologic cancer patients [101] .

As the COVID-19 pandemic could last a long time, hematologists should be aware of the risk of superinfections in COVID-19 hematologic cancer patients, particularly in those neutropenic and treated with steroids. A systematic workup of diagnostic tests for fungal infections should be always performed in these patients.

-COVID-19-associated pulmonary aspergillosis (CAPA) has been well described in patients admitted in ICU, while very few data are available in hematologic patients. -

The prognosis of hematologic patients with COVID-19 is extremely poor with mortality rates approaching 30% in many studies, and the outcome is even worse among patients with CAPA -Hematologic patients with COVID-19 infection should be investigated thoroughly for the possible coexistence of IFI.

Viral infections and IFI as single entities are well-described complications in patients affected by hematologic malignancies. By contrast, the coexistence of virus and fungi may represent a deceptive clinical issue. A great variety of viruses have been reported to be associated with fungi, almost exclusively represented by mold infections. Among HMs, HSCT recipients are the subjects at the highest risk of viral and IFI co-infections. Early interventions in terms of an accurate diagnostic work-up are of upmost importance to unveil this complication and adopt an appropriate therapeutic strategy. Whenever feasible, prioritization of vaccination programs is of paramount importance, although hematologic patients are not expected to generate robust responses. Further studies including a larger cohort of hematologic patients are eagerly needed to assess the impact of viral and IFI co-infections on the outcome of the patients.

Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM (Sorveglianza Epidemiologica Infezioni Fungine nelle Emopatie Maligne) recommendations

Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients

Association between CMV and Invasive Fungal Infections after Autologous Stem Cell Transplant in Lymphoproliferative Malignancies: Opportunistic Partnership or Cause-Effect Relationship?

Cytomegalovirus Reactivation is Associated with Increased Risk of Late-Onset Invasive Fungal Disease Following Allogeneic Hematopoietic Stem Cell Transplantation; a Multi-Centre Study in the Current Era of Viral Load Monitoring

Incidence, risk factors, and outcome of pulmonary invasive fungal disease after respiratory virus infection in allogeneic hematopoietic stem cell transplantation recipients

Defining and managing COVID-19-associated pulmonary aspergillosis: The 2020 ECMM/ISHAM consensus criteria for research and clinical guidance

Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the

Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant

Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: A phase 3, double-blind, placebo-controlled, randomised trial

CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation

Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation

Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: A randomized trial

Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation

Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: A retrospective cohort study

Reduced mortality after allogeneic hematopoietic-cell transplantation

Cytomegalovirus reactivation following autologous peripheral blood stem cell transplantation for multiple myeloma patients in the era of novel chemotherapeutics and tandem transplantation

The potential role of pre-transplant HBcIgG seropositivity as predictor of clinically relevant Cytomegalovirus infection in patients with lymphoma undergoing autologous hematopoietic stem cell transplantation: A study from the Rome Transplant Network

Evaluation of risk of symptomatic cytomegalovirus reactivation in myeloma patients treated with tandem autologous stem cell transplantation and novel agents: A single-institution study

Cytomegalovirus reactivation in patients with hematological diseases and after autologous stem cell transplantation as consolidation: A single-center study

Cytomegalovirus infection in autologous stem cell transplant recipients in the era of Rituximab

Prospective surveillance vs. clinically driven approach for CMV reactivation after autologous stem cell transplant

Cytomegalovirus reactivation in adult recipients of autologous stem cell transplantation: A single center experience

Cytomegalovirus reactivation in patients with multiple myeloma

Prospective cytomegalovirus monitoring during first-line chemotherapy in patients with acute myeloid leukemia

Impact of intensity of the pre-transplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: A retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

Epidemiology of invasive mold infections in allogeneic stem cell transplantation recipients: Biological risk factors for infection according to time after transplantation

Lower respiratory tract respiratory virus infections increase the risk of invasive aspergillosis after a reduced-intensity allogeneic hematopoietic SCT

Invasive fungal infection in allogeneic hematopoietic stem cell transplantation recipients: Single center experiences of 12 years

Association between the kinetics of cytomegalovirus reactivation evaluated in terms of the area under the curve of cytomegalovirus antigenemia and invasive mold infection during the post-engraftment phase after allogeneic hematopoietic stem cell transplantation

Risk factors for invasive mold diseases in allogeneic hematopoietic cell transplant recipients

Risk factors for invasive mold infections following allogeneic hematopoietic stem cell transplantation: A single center study of 190 recipients. Scand

Risk factors and prognosis of invasive fungal infections in allogeneic stem cell transplantation recipients: A single institution experience

Risk factors for invasive aspergillosis and related mortality in recipients of allogeneic SCT from alternative donors: An analysis of 306 patients

Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloblative conditioning

Incidence and outcome of invasive fungal diseases after allogeneic stem cell transplantation: A prospective study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

An investigation on the relationship between occurrence of CMV DNAemia and the development of invasive aspergillosis in the allogeneic stem cell transplantation setting

A risk prediction score for invasive mold disease in patients with hematologic malignancies

Human cytomegalovirus paralyzes macrophage motility through down.regulation of chemokine receptors, reorganization of the cytoskeleton, and release of macrophage migration inhibitory factors

Invasive fungal disease and cytomegalovirus infection: Is there an association?

Outcomes and prognostic factors of non-HIV patients with Pneumocystiis jirovecii pneumonia and pulmonary CMV co-infection: A retrospective cohort study

Invasive pulmonary aspergillosis complicating severe influenza: Epidemiology, diagnosis and treatment

Epidemiology, Diagnosis, Treatment, and Prevention of Influenza Infection in Oncology Patients

Respiratory Virus Infections of the Stem Cell Transplant Recipient and the Hematologic Malignancy Patient

Outcomes in Invasive Pulmonary Aspergillosis Infections Complicated by Respiratory Viral Infections in Patients with Hematologic Malignancies: A Case-Control Study

Invasive pulmonary aspergillosis in patients with influenza infection: A retrospective study and review of the literature

Influenza-Associated Pulmonary Aspergillosis: A Local or Global Lethal Combination?

Higher mortality of severe influenza patients with probable aspergillosis than those with and without other coinfections

Detection of invasive aspergillosis in critically ill patients with influenza: The role of plasma galactomannan

Vaccine response following anti-CD20 therapy: A systematic review and meta-analysis of 905 patients

Respiratory viral infections in solid organ and hematopoietic stem cell transplantation

Changing epidemiology of respiratory viral infections in hematopoietic cell transplant recipients and solid organ transplant recipients

Human parainfluenza virus type 3 infections in patients with hematopoietic stem cell transplants: The mode of nosocomial infections and prognosis

Clinical outcomes associated with respiratory virus detection before allogeneic hematopoietic stem cell transplant

Upper and lower respiratory tract infections by human enterovirus and rhinovirus in adult patients with hematological malignancies

Human parainfluenza virus infection after hematopoietic stem cell transplantation: Risk factors, management, mortality, and changes over time

Respiratory virus infections after stem cell transplantation: A prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies

Incidence and predictors of respiratory viral infections by multiplex PCR in allogeneic hematopoietic cell transplant recipients 50 years and older including geriatric assessment

Mortality rates of human metapneumovirus and respiratory syncytial virus lower respiratory tract infections in hematopoietic cell transplantation recipients

A multicenter consortium to define the epidemiology and outcomes of inpatient respiratory viral infections in pediatric hematopoietic stem cell transplant recipients

Strong association between respiratory viral infection early after hematopoietic stem cell transplantation and the development of life-threatening acute and chronic alloimmune lung syndromes

Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: The Fred Hutchinson Cancer Research Center experience

Respiratory virus pneumonia after hematopoietic cell transplantation (HCT): Associations between viral load in bronchoalveolar lavage samples, viral RNA detection in serum samples, and clinical outcomes of HCT

Polymicrobial pulmonary infection in patients with hematological malignancies: Prevalence, co-pathogens, course and outcome

Low prevalence of human metapneumovirus and human bocavirus in adult immunocompromised high risk patients suspected to suffer from Pneumocystis pneumonia

Invasive fungal infections associated with prior respiratory viral infections in immunocompromised hosts

Thin-section CT findings in hematopoietic stem cell transplantation recipients with respiratory virus pneumonia

Clinical characteristics and outcome associated with pandemic (2009) H1N1 influenza infection in patients with hematologic malignancies: A retrospective cohort study

Viral pneumonia after hematopoietic stem cell transplantation: High-resolution CT findings

Chest CT features of communityacquired respiratory viral infections in adult inpatients with lower respiratory tract infections

CT of viral lower respiratory tract infections in adults: Comparison among viral organisms and between viral and bacterial infections

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

COVID-19 Associated Candidiasis (CAC): An Underestimated Complication in the Absence of Immunological Predispositions?

COVID-19 Associated Pulmonary Aspergillosis: Do We Have the CAPAcity to Improve Outcomes?

Incidence and mortality of COVID-19-associated pulmonary aspergillosis: A systematic review and meta-analysis

Invasive fungal infections in patients with COVID-19: A review on pathogenesis, epidemiology, clinical features, treatment, and outcomes

Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India

Invasive Pulmonary Aspergillosis in Patients with SARS-CoV-2 Infection: A Systematic Review of the Literature

Multi-triazole-resistant Aspergillus fumigatus and SARS-CoV-2 co-infection: A lethal combination

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: A retrospective, multicentre, cohort study

Clinical characteristics and risk factors for mortality in hematologic patients affected by COVID-19

Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System

COVID-19 outcomes in patients with hematologic disease

Clinical outcome of coronavirus disease 2019 in haemato-oncology patients

Impact of hematologic malignancy and type of cancer therapy on COVID-19 severity and mortality: Lessons from a large population-based registry study

Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: An observational cohort study

Clinical course and risk factors for mortality from COVID-19 in patients with haematological malignancies

Clinical characteristics, therapeutic management, and prognostic factors of adult COVID-19 inpatients with hematological malignancies

Fatal Invasive Aspergillosis and Coronavirus Disease in an Immunocompetent Patient

Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19

Successfully treated severe COVID-19 and invasive aspergillosis in early hematopoietic cell transplantation setting

Fatal Invasive Pulmonary Aspergillosis in COVID-19 Patient with Acute Myeloid Leukemia in Iran

SARS-CoV-2 Working Group. Isolation of Aspergillus spp. in respiratory samples of patients with COVID-19 in a Spanish Tertiary Care Hospital

Characteristics and outcomes of patients with cancer and COVID-19: Results from a cohort study

Autopsy Proven Pulmonary Mucormycosis Due to Rhizopus microsporus in a Critically Ill COVID-19 Patient with Underlying Hematological Malignancy

Mixed mold infection with Aspergillus fumigatus and Rhizopus microsporus in a severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) patient

COVID-19-associated mucormycosis: Case report and systematic review

Co-infections and superinfections complicating COVID-19 in cancer patients: A multicentre, international study

Nosocomial outbreak of SARS-CoV-2 infection in a haematological unit-High mortality rate in infected patients with haematologic malignancies