Invasive Pulmonary Aspergillosis in Hospitalized Hematopoietic Stem Cell Transplantation Recipients: Outcomes Based on the United States National Readmission Database.

BACKGROUND AND OBJECTIVE: Hematopoietic stem cell transplant (HSCT) is a well-established treatment for hematologic malignancies and certain autoimmune and congenital conditions. HSCT is associated with immunocompromise and increased risk of infections. This study assessed whether invasive pulmonary aspergillosis (IPA) affects in-hospital mortality and 30-day readmission among HSCT patients. A secondary objective was to examine potential differences in complications between HSCT with and without IPA. MATERIALS AND METHODS: A retrospective study of a nationally representative cohort of hospital admissions was conducted, with data collected from the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project Nationwide Readmissions Database between 2013 and 2019. The International Classification of Diseases, 10th revision (ICD-10), and 9th revision (ICD-9) diagnostic codes were used to identify patients with IPA and HSCT. All adult patients ≥18 years were included in the study. RESULTS: There were 90,451 hospitalizations for HSCT from 2013 to 2019; 89,331 (98.8%) had HSCT without IPA, while 1092 (1.2%) hospitalizations had HSCT with IPA. The in-hospital mortality for HSCT-IPA was higher compared to HSCT without IPA (18.3% vs. 4.2%; p < 0.001). HSCT-IPA had a significantly higher 30-day readmission rate (36.2%) than that of HSCT without IPA (24.0%). HSCT-IPA also had a higher mean cost of admission ($303,437) than that of HSCT without IPA ($57,587).The HSCT-IPA group had higher multi-organ complications, including respiratory failure (51.3% vs. 13.5%, p < 0.001), sepsis (38.2% vs. 18.5%, p < 0.001), septic shock (16.1% vs. 5.1%, p < 0.001), need for mechanical ventilation (21.1% vs. 5.1% p < 0.001), non-invasive positive pressure ventilation (4.9% vs. 2.5%, p < 0.001), and intensive-care unit admission (21.8% vs. 6.1% p < 0.001). CONCLUSION: IPA is a rare but severe complication associated with HSCT, with higher in-hospital mortality, complications due to multi-organ failure, readmission rates, and cost of hospitalization when compared to HSCT without IPA.

Left atrial thrombosis with invasive pulmonary aspergillosis in children with immunodeficiency.

Invasive aspergillosis is a major cause of infectious disease in immunocompromised patients; however, cardiac involvement in pulmonary aspergillosis is not well-known. Two paediatric patients undergoing chemotherapy were diagnosed with cardiac aspergilloma, accompanied by pulmonary aspergillosis. In both patients, antibiotic and antifungal treatments were initiated immediately after the pneumonia was diagnosed; however, both died of multiple cerebral thromboembolisms.

Invasive Pulmonary Aspergillosis Successfully Treated with Granulocyte Transfusions Followed by Hematopoietic Stem Cell Transplantation in a Patient with Severe Childhood Aplastic Anemia.

Granulocyte transfusions (GTX) have been used in patients with neutropenia or neutropenia associated with invasive fungal infection. An 11-year-old girl with severe aplastic anemia (SAA) received immunosuppressive therapy (IST) with rabbit antithymocyte globulin, cyclosporine, and granulocyte colony-stimulating factor. However, IST was not effective and her condition became complicated with life-threatening invasive pulmonary aspergillosis. Owing to the necessity for early neutrophil recovery to resolve the infection, GTX were performed, followed by bone marrow transplantation (BMT) from her mother with human leukocyte antigen-B locus mismatch. Her dyspnea improved and she eventually became afebrile after the initiation of GTX. Despite engraftment failure following BMT, successful engraftment was achieved by salvage therapy with peripheral blood stem cell transplantation. Chest computed tomography scan obtained 4 months after BMT revealed marked improvement in pneumonia. The current case illustrates that GTX may be useful in controlling invasive fungal infections before hematopoietic stem cell transplantation in patients with SAA.

CAR T cells targeting Aspergillus fumigatus are effective at treating invasive pulmonary aspergillosis in preclinical models.

Aspergillus fumigatus is a ubiquitous mold that can cause severe infections in immunocompromised patients, typically manifesting as invasive pulmonary aspergillosis (IPA). Adaptive and innate immune cells that respond to A. fumigatus are present in the endogenous repertoire of patients with IPA but are infrequent and cannot be consistently isolated and expanded for adoptive immunotherapy. Therefore, we gene-engineered A. fumigatus-specific chimeric antigen receptor (Af-CAR) T cells and demonstrate their ability to confer antifungal reactivity in preclinical models in vitro and in vivo. We generated a CAR targeting domain AB90-E8 that recognizes a conserved protein antigen in the cell wall of A. fumigatus hyphae. T cells expressing the Af-CAR recognized A. fumigatus strains and clinical isolates and exerted a direct antifungal effect against A. fumigatus hyphae. In particular, CD8+ Af-CAR T cells released perforin and granzyme B and damaged A. fumigatus hyphae. CD8+ and CD4+ Af-CAR T cells produced cytokines that activated macrophages to potentiate the antifungal effect. In an in vivo model of IPA in immunodeficient mice, CD8+ Af-CAR T cells localized to the site of infection, engaged innate immune cells, and reduced fungal burden in the lung. Adoptive transfer of CD8+ Af-CAR T cells conferred greater antifungal efficacy compared to CD4+ Af-CAR T cells and an improvement in overall survival. Together, our study illustrates the potential of gene-engineered T cells to treat aggressive infectious diseases that are difficult to control with conventional antimicrobial therapy and support the clinical development of Af-CAR T cell therapy to treat IPA.

COVID-19-associated aspergillosis in a Brazilian referral centre: Diagnosis, risk factors and outcomes.

BACKGROUND: COVID-19 patients on mechanical ventilation are at risk to develop invasive aspergillosis. To provide additional data regarding this intriguing entity, we conducted a retrospective study describing risk factors, radiology and prognosis of this emerging entity in a Brazilian referral centre. METHODS: This retrospective study included intubated (≥18 years) patients with COVID-19 admitted from April 2020 until July 2021 that had bronchoscopy to investigate pulmonary co-infections. COVID-19-associated aspergillosis (CAPA) was defined according to the 2020 European Confederation of Medical Mycology/International Society of Human and Animal Mycosis consensus criteria. The performance of tracheal aspirate (TA) cultures to diagnose CAPA were described, as well as the radiological findings, risk factors and outcomes. RESULTS: Fourteen patients (14/87, 16%) had probable CAPA (0.9 cases per 100 ICU admissions). The sensitivity, specificity, positive predictive value and negative predictive value of TA for the diagnosis of CAPA were 85.7%, 73.1%, 46.2% and 95% respectively. Most of the radiological findings of CAPA were classified as typical of invasive pulmonary aspergillosis (64.3%). The overall mortality rate of probable CAPA was 71.4%. Age was the only independent risk factor for CAPA [p = .03; odds ratio (OR) 1.072]. CAPA patients under renal replacement therapy (RRT) may have a higher risk for a fatal outcome (p = .053, hazard ratio 8.047). CONCLUSIONS: CAPA was a prevalent co-infection in our cohort of patients under mechanical ventilation. Older patients had a higher risk to develop CAPA, and a poor prognosis may be associated with RRT.

Hematopoietic Stem Cell Transplantation Cures Therapy-refractory Aspergillosis in Chronic Granulomatous Disease.

BACKGROUND: Pulmonary invasive aspergillosis is a frequent and life-threatening complication for patients with chronic granulomatous disease (CGD). Despite combined treatment with several groups of antifungal agents, conservative treatment of invasive aspergillosis often remains refractory. Pulmonary invasive aspergillosis is often treated by surgical resection of consolidated lobes or segments, donor granulocyte transfusions and allogeneic hematopoietic stem cell transplantation (HSCT). These options are not mutually exclusive and often combined. METHODS AND RESULTS: We here describe the treatment of 3 patients with CGD who received HSCT upon active pulmonary invasive aspergillosis: Two of them received HSCT as salvage therapy for refractory aspergillosis, and 1 patient received elective HSCT in infancy but developed pulmonary aspergillosis during secondary graft failure. Based on our experience and available literature, we discuss indication as well as timing of HSCT, granulocyte transfusions and surgery in patients with CGD and pulmonary invasive aspergillosis. CONCLUSIONS: Upon diagnosis with invasive aspergillosis in CGD, we propose to start antifungal treatment and preparation for HSCT at the same time. Remission of pulmonary invasive aspergillosis before HSCT remains preferable but is not mandatory. When pulmonary aspergillosis in patients with CGD remains refractory for longer than 3 months on conservative treatment, HSCT without prior surgery or accompanying granulocyte transfusions is a feasible option.

Clinical utility of the updated European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and the Mycoses Study Group Education and Research Consortium computed tomography criteria of invasive pulmonary aspergillosis in hematological malignancies.

Invasive pulmonary aspergillosis is a life-threatening complication in the cases of patients with hematologic malignancies. In December 2019, the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and the Mycoses Study Group Education and Research Consortium published a revision and an update of the consensus definitions of invasive fungal disease. The aim of this study was to evaluate the signs and radiologic patterns of early-stage invasive pulmonary aspergillosis in computed tomography in patients with hematologic entities according to the latest criteria.This retrospective analysis of a baseline high-resolution computed tomography included neutropenic patients with hematological malignancies and probable invasive pulmonary aspergillosis. The data were collected between the years 2017 and 2019. Computed tomography was performed within 72 h from the beginning of clinical symptoms: fever, dyspnea or nonproductive cough. CT scans were analyzed by two independent radiologists according to the standardized protocol based on predefined criteria.All 35 evaluated patients had typical lesions for early-stage invasive aspergillosis. Wedge-shaped infiltrates were noted in 48.6% of patients. In this group, 40% of patients had coexisting atypical radiological findings. In 11.4% of patients, wedge-shape consolidations were noted as the only type of lesions.Employment of the latest EORTC/MSG criteria increased diagnostic value of the baseline high resolution computed tomography in our study group by 11.4%.

Invasive pulmonary aspergillosis associated with viral pneumonitis.

The occurrence of invasive pulmonary aspergillosis (IPA) in critically ill patients with viral pneumonitis has increasingly been reported in recent years. Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are the two most common forms of this fungal infection. These diseases cause high mortality in patients, most of whom were previously immunocompetent. The pathogenesis of IAPA and CAPA is still not fully understood, but involves viral, fungal and host factors. In this article, we discuss several aspects regarding IAPA and CAPA, including their possible pathogenesis, the use of immunotherapy, and future challenges.

Invasive aspergillosis in solid organ transplantation: Diagnostic challenges and differences in outcome in a Spanish national cohort (Diaspersot study).

BACKGROUND: The diagnosis of invasive aspergillosis (IA) can be problematic in solid organ transplantation (SOT). The prognosis greatly varies according to the type of transplant, and the impact of prophylaxis is not well defined. PATIENTS AND METHODS: The Diaspersot cohort analyses the impact of IA in SOT in Spain during the last 10 years. Proven and probable/putative IA was included. RESULTS: We analysed 126 cases of IA. The incidences of IA were as follows: 6.5%, 2.9%, 1.8% and 0.6% for lung, heart, liver and kidney transplantation, respectively. EORTC/MSG criteria confirmed only 49.7% of episodes. Tree-in-bud sign or ground-glass infiltrates were present in 56.3% of patients, while serum galactomannan (optical density index >0.5) was positive in 50.6%. A total of 41.3% received combined antifungal therapy. Overall mortality at 3 months was significantly lower (p < 0.001) in lung transplant recipients (14.8%) than in all other transplants [globally: 48.6%; kidney 52.0%, liver 58.3%, heart 31.2%, and combined 42.9%]. Fifty-four percent of episodes occurred despite the receipt of antifungal prophylaxis, and in 10%, IA occurred during prophylaxis (breakthrough infection), with both nebulised amphotericin (in lung transplant recipients) and candins (in the rest). CONCLUSIONS: Invasive aspergillosis diagnostic criteria, applied to SOT patients, may differ from those established for haematological patients. IA in lung transplants has a higher incidence, but is associated with a better prognosis than other transplants. Combination therapy is frequently used for IA in SOT. Prophylactic measures require optimisation of its use within this population.

Incidence, diagnosis and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA): a systematic review.

COVID-19-associated pulmonary aspergillosis (CAPA) is defined as invasive pulmonary aspergillosis occurring in COVID-19 patients. The purpose of this review was to discuss the incidence, characteristics, diagnostic criteria, biomarkers, and outcomes of hospitalized patients diagnosed with CAPA. A literature search was performed through Pubmed and Web of Science databases for articles published up to 20th March 2021. In 1421 COVID-19 patients, the overall CAPA incidence was 13.5% (range 2.5-35.0%). The majority required invasive mechanical ventilation (IMV). The time to CAPA diagnosis from illness onset varied between 8.0 and 16.0 days. However, the time to CAPA diagnosis from intensive care unit (ICU) admission and IMV initiation ranged between 4.0-15.0 days and 3.0-8.0 days. The most common diagnostic criteria were the modified AspICU-Dutch/Belgian Mycosis Study Group and IAPA-Verweij et al. A total of 77.6% of patients had positive lower respiratory tract cultures, other fungal biomarkers of bronchoalveolar lavage and serum galactomannan were positive in 45.3% and 18.2% of patients. The CAPA mortality rate was high at 48.4%, despite the widespread use of antifungals. Lengthy hospital and ICU stays ranging between 16.0-37.5 days and 10.5-37.0 days were observed. CAPA patients had prolonged IMV duration of 13.0-20.0 days. The true incidence of CAPA likely remains unknown as the diagnosis is limited by the lack of standardized diagnostic criteria that rely solely on microbiological data with direct or indirect detection of Aspergillus in respiratory specimens, particularly in clinical conditions with a low pretest probability. A well-designed, multi-centre study to determine the optimal diagnostic approach for CAPA is required.

[Invasive fungal infections in ICU patients - What's New?] / Invasive Pilzinfektionen bei Intensivpatienten ­ Was gibt es Neues?

Invasive fungal infections are gaining increasing importance in intensive care medicine. The aim of this article is to present an update on recent developments in the field of invasive fungal infection in critically ill patients. Particular emphasis is placed on the recently described invasive mold infections in patients with acute respiratory distress syndrome due to influenza or COVID-19. Detecting high-risk patients and the optimal diagnostic and therapeutic strategies play a decisive role to improve outcome.

COVID-19-associated invasive pulmonary aspergillosis in a tertiary care center in Mexico City.

Invasive pulmonary aspergillosis (IPA) is a severe infection caused by aspergillus sp. that usually develops in patients with severe immunosuppression. IPA has been recently described in critically ill COVID-19 patients (termed as COVID-associated pulmonary aspergillosis, or CAPA) that are otherwise immunocompetent. In order to describe the characteristics of patients with CAPA, we conducted a retrospective cohort study in a tertiary care center in Mexico City. We included all patients with confirmed COVID-19 admitted to the intensive care unit that had serum or bronchoalveolar lavage galactomannan measurements. We used the criteria proposed by Koehler et al. to establish the diagnosis of CAPA. Main outcomes were the need for invasive mechanical ventilation (IMV) and in-hospital mortality. Out of a total of 83 hospitalized patients with COVID-19 in the ICU, 16 (19.3%) met the criteria for CAPA. All patients diagnosed with CAPA required IMV whereas only 84% of the patients in the non-IPA group needed this intervention (P = 0.09). In the IPA group, 31% (n = 5) of the patients died, compared to 13% (n = 9) in the non-CAPA group (P = 0.08). We conclude that CAPA is a frequent co-infection in critically ill COVID-19 patients and is associated with a high mortality rate. The timely diagnosis and treatment of IPA in these patients is likely to improve their outcome. LAY SUMMARY: We studied the characteristics of patients with COVID-19-associated invasive pulmonary aspergillosis (CAPA). Patients with CAPA tended to need invasive mechanical ventilation more frequently and to have a higher mortality rate. Adequate resources for its management can improve their outcome.

SARS-CoV-2 and Aspergillus section Fumigati coinfection in an immunocompetent patient treated with corticosteroids.

BACKGROUND: Patients with severe viral pneumonia are likely to receive high-dose immunomodulatory drugs to prevent clinical worsening. Aspergillus species have been described as frequent secondary pneumonia agents in severely ill influenza patients receiving steroids. COVID-19 patients admitted to Intensive Care Unit (ICU) are receiving steroids as part of their treatment and they share clinical characteristics with other patients with severe viral pneumonias. COVID-19 patients receiving steroids should be considered a putative risk group of invasive aspergillosis. CASE REPORT: We are reporting a SARS-CoV-2/Aspergillus section Fumigati coinfection in an elderly intubated patient with a history of pulmonary embolism treated with corticosteroids. The diagnosis was made following the ad hoc definitions described for patients admitted to ICU with severe influenza, including clinical criteria (fever for 3 days refractory to the appropriate antibiotic therapy, dyspnea, pleural friction rub, worsening of respiratory status despite antibiotic therapy and need of ventilator support), a radiological criterion (pulmonary infiltrate) and a mycological criterion (several positive galactomannan tests on serum with ratio ≥0.5). In addition, Aspergillus section Fumigati DNA was found in serum and blood samples. These tests were positive 4 weeks after the patient was admitted to the ICU. The patient received voriconazole and after two month in ICU his respiratory status improved; he was discharged after 6 weeks of antifungal treatment. CONCLUSIONS: Severely ill COVID-19 patients would be considered a new aspergillosis risk group. Galactomannan and Aspergillus DNA detection would be useful methods for Aspergillus infection diagnosis as they allow avoiding the biosafety issues related to these patients.

Putative invasive pulmonary aspergillosis in critically ill patients with COVID-19: An observational study from New York City.

BACKGROUND: Critically ill patients with coronavirus disease-2019 (COVID-19) are at the theoretical risk of invasive pulmonary aspergillosis (IPA) due to known risk factors. PATIENTS/METHODS: We aimed to describe the clinical features of COVID-19-associated pulmonary aspergillosis at a single centre in New York City. We performed a retrospective chart review of all patients with COVID-19 with Aspergillus isolated from respiratory cultures. RESULTS: A total of seven patients with COVID-19 who had one or more positive respiratory cultures for Aspergillus fumigatus were identified, all of whom were mechanically ventilated in the ICU. Four patients were classified as putative IPA. The median age was 79 years, and all patients were male. The patients had been mechanically ventilated for a mean of 6.8 days (range: 1-14 days) before Aspergillus isolation. Serum galactomannan level was positive for only one patient. The majority of our cases received much higher doses of glucocorticoids than the dosage with a proven mortality benefit. All four patients died. CONCLUSIONS: Vigilance for secondary fungal infections will be needed to reduce adverse outcomes in critically ill patients with COVID-19.

Fungal Co-infections Associated with Global COVID-19 Pandemic: A Clinical and Diagnostic Perspective from China.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been sweeping across the globe. Based on a retrospective analysis of SARS and influenza data from China and worldwide, we surmise that the fungal co-infections associated with global COVID-19 might be missed or misdiagnosed. Although there are few publications, COVID-19 patients, especially severely ill or immunocompromised, have a higher probability of suffering from invasive mycoses. Aspergillus and Candida infections in COVID-19 patients will require early detection by a comprehensive diagnostic intervention (histopathology, direct microscopic examination, culture, (1,3)-ß-D-glucan, galactomannan, and PCR-based assays) to ensure effective treatments. We suggest it is prudent to assess the risk factors, the types of invasive mycosis, the strengths and limitations of diagnostic methods, clinical settings, and the need for standard or individualized treatment in COVID-19 patients. We provide a clinical flow diagram to assist the clinicians and laboratory experts in the management of aspergillosis, candidiasis, mucormycosis, or cryptococcosis as co-morbidities in COVID-19 patients.

Pulmonary Aspergillosis: What the Generalist Needs to Know.

Aspergillus spp. is a ubiquitous mold found commonly in our environment that can cause a spectrum of pulmonary disorders, ranging from a hypersensitivity reaction to an acutely invasive disease with significant mortality. Allergic bronchopulmonary aspergillosis results from airway hypersensitivity from aspergillus colonization almost exclusively in patients with asthma and cystic fibrosis. Chronic pulmonary aspergillosis typically presents in immunocompetent patients with underlying lung pathology. Treatment is primarily with antifungal agents; however, other measures such as surgical resection may be necessary. Invasive pulmonary aspergillosis is a severe infection in immunocompromised patients and is characterized by invasion of pulmonary vasculature by the Aspergillus hyphae. Recent advances in the diagnosis and management of invasive pulmonary aspergillosis include emerging risk factors such as critically ill patients, and those with chronic obstructive pulmonary disease and liver disease. In addition, noninvasive biomarkers have made it easier to suspect and diagnose invasive pulmonary aspergillosis. There are more effective and better-tolerated antifungal agents that have improved patient outcomes. This review introduces the spectrum of pulmonary aspergillosis geared toward generalists, including disease manifestations, most recent diagnostic criteria, and first-line treatment options. Involving a multidisciplinary team is vital to the early diagnosis and management of these diseases.

Invasive pseudomembranous upper airway and tracheal Aspergillosis refractory to systemic antifungal therapy and serial surgical debridement in an Immunocompetent patient.

BACKGROUND: The development of respiratory infections secondary to Aspergillus spp. spores found ubiquitously in the ambient environment is uncommon in immunocompetent patients. Previous reports of invasive upper airway aspergillosis in immunocompetent patients have generally demonstrated the efficacy of treatment regimens utilizing antifungal agents in combination with periodic endoscopic debridement, with symptoms typically resolving within months of initiating therapy. CASE PRESENTATION: A 43-year-old previously healthy female presented with worsening respiratory symptoms after failing to respond to long-term antibiotic treatment of bacterial sinusitis. Biopsy of her nasopharynx and trachea revealed extensive fungal infiltration and Aspergillus fumigatus was isolated on tissue culture. Several months of oral voriconazole monotherapy failed to resolve her symptoms and she underwent mechanical debridement for symptom control. Following transient improvement, her symptoms subsequently returned and failed to fully resolve in spite of increased voriconazole dosing and multiple additional tissue debridements over the course of many years. CONCLUSIONS: Invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients. In the rare instances that such infections do occur, combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach. However, some patients may continue to experience refractory symptoms. In such cases, continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved.

Understanding the immunology of asthma: Pathophysiology, biomarkers, and treatments for asthma endotypes.

Asthma is a common disease in paediatrics and adults with a significant morbidity, mortality, and financial burden worldwide. Asthma is now recognized as a heterogeneous disease and emerging clinical and laboratory research has elucidated understanding of asthma's underlying immunology. The future of asthma is classifying asthma by endotype through connecting discernible characteristics with immunological mechanisms. This comprehensive review of the immunology of asthma details the currently known pathophysiology and clinical practice biomarkers in addition to forefront biologic and targeted therapies for all of the asthma endotypes. By understanding the immunology of asthma, practitioners will be able to diagnose patients by asthma endotype and provide personalized, biomarker-driven treatments to effectively control patients' asthma.