The role of surgery for invasive pulmonary aspergillosis in paediatric hemato-oncology patients-Can we better define it?

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a serious condition with high morbidity and mortality in paediatric patients with cancer, haematological diseases or immunodeficiencies with or without allogeneic haematopoietic stem cell transplantation (HSCT). The role of surgical intervention for the management of IPA has scarcely been investigated. OBJECTIVES: The aim of this study was to present a single center experience of management of IPA in paediatric patients of an oncological ward, to determine the short and long-term outcomes after thoracic surgical interventions, and to outline the indications of surgical interventions in selected patients. PATIENTS/METHODS: We conducted a retrospective study of 44 paediatric patients with proven and probable IPA treated in our institution between January 2003 and December 2021. The primary endpoint was the overall survival after surgical interventions. Secondary endpoints included post-operative morbidity and mortality. RESULTS: The median age at diagnosis of IPA in our cohort was 11.79 years (range 0.11-19.6). The underlying conditions were malignancies in 34 (77%) patients and haematological or immunological disorders with allogeneic HSCT in 9 (23%) patients. We performed thoracic surgical interventions in 10 (22.7%) patients. Most patients received a video assisted thoracic surgery. Only one patient died within 90 days after surgery with a median follow-up time of 50 months. No other major post-operative complications occurred. The calculated 5-year survival rate from IPA for patients after surgical intervention with curative intention was 57% and 56% for patients without (p = .8216). CONCLUSIONS: IPA resulted in relevant morbidity and mortality in our paediatric patient cohort. Thoracic surgical interventions are feasible and may be associated with prolonged survival as a part of multidisciplinary approach in selected paediatric patients with IPA. Larger scale studies are necessary to investigate the variables associated with the necessity of surgery.

A Pathology-based Case Series of Influenza- and COVID-19-associated Pulmonary Aspergillosis: The Proof Is in the Tissue.

Rationale: Invasive pulmonary aspergillosis has emerged as a frequent coinfection in severe coronavirus disease (COVID-19), similarly to influenza, yet the clinical invasiveness is more debated. Objectives: We investigated the invasive nature of pulmonary aspergillosis in histology specimens of influenza and COVID-19 ICU fatalities in a tertiary care center. Methods: In this monocentric, descriptive, retrospective case series, we included adult ICU patients with PCR-proven influenza/COVID-19 respiratory failure who underwent postmortem examination and/or tracheobronchial biopsy during ICU admission from September 2009 until June 2021. Diagnosis of probable/proven viral-associated pulmonary aspergillosis (VAPA) was made based on the Intensive Care Medicine influenza-associated pulmonary aspergillosis and the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) COVID-19-associated pulmonary aspergillosis consensus criteria. All respiratory tissues were independently reviewed by two experienced pathologists. Measurements and Main Results: In the 44 patients of the autopsy-verified cohort, 6 proven influenza-associated and 6 proven COVID-19-associated pulmonary aspergillosis diagnoses were identified. Fungal disease was identified as a missed diagnosis upon autopsy in 8% of proven cases (n = 1/12), yet it was most frequently found as confirmation of a probable antemortem diagnosis (n = 11/21, 52%) despite receiving antifungal treatment. Bronchoalveolar lavage galactomannan testing showed the highest sensitivity for VAPA diagnosis. Among both viral entities, an impeded fungal growth was the predominant histologic pattern of pulmonary aspergillosis. Fungal tracheobronchitis was histologically indistinguishable in influenza (n = 3) and COVID-19 (n = 3) cases, yet macroscopically more extensive at bronchoscopy in influenza setting. Conclusions: A proven invasive pulmonary aspergillosis diagnosis was found regularly and with a similar histological pattern in influenza and in COVID-19 ICU case fatalities. Our findings highlight an important need for VAPA awareness, with an emphasis on mycological bronchoscopic work-up.

Autopsy study of fatal invasive pulmonary aspergillosis: Often undiagnosed premortem.

Invasive aspergillosis (IA) is a serious complication in immunocompromised and critically ill patients but is difficult to diagnose. We sought to examine how often cases go undiagnosed and to understand the presenting clinical and radiologic features associated with fatal IA. We reviewed cases of fatal IA confirmed at autopsy (N = 67) between 1999 and 2019 at a tertiary academic hospital. At autopsy, pulmonary involvement was present in 97% of cases--46% were limited to the lungs and 51% had concomitant extrapulmonary involvement. Immunosuppression with either glucocorticoids and/or other immunosuppressive agents was present in 85%. Among those not immunocompromised (15%), chronic lung disease was present in 70%, and a respiratory coinfection was found in 50%. Chest imaging abnormalities including consolidation, ground glass opacities, halo sign, cavitation, and air crescent sign were present in 49%, 49%, 37%, 22%, and 7% of cases, respectively. Diagnostic bronchoscopy was performed in 61% of cases and yielded aspergillus in 63% of those cases by either bronchoalveolar lavage (galactomannan and/or culture), bronchial washings, or transbronchial biopsy cultures. Either a respiratory coinfection or other systemic coinfection was diagnosed in 64%. The performance of diagnostic bronchoscopy was associated with accurate pre-mortem identification of IA (p = 0.001). Clinicians correctly identified IA as the cause of death in only 27% of fatal IA cases identified at autopsy. Complex presenting features, high rates of co-infections, and low rates of invasive diagnostic procedures may have led to missed diagnoses of IA.

Incidence, risk factors and mortality of invasive pulmonary aspergillosis in patients with influenza: A systematic review and meta-analysis.

BACKGROUND: An increasing number of cases of invasive pulmonary aspergillosis (IPA) complicating influenza have been described. We performed a meta-analysis to estimate the incidence, risk factors and outcomes of IPA in patients with influenza. METHODS: A systematic search was conducted in the PubMed, EMBASE and Cochrane Library databases from their inception to 31 August 2021 for eligible studies. Data on the incidence and risk factors of and mortality due to IPA in influenza patients were pooled using a random-effects model. Sensitivity analyses restricted to severe influenza requiring intensive care unit (ICU) support and multiple subgroup analyses were performed. RESULTS: Fourteen studies involving 6024 hospitalised patients with influenza were included. IPA was estimated to occur in 10% of influenza patients, with a mortality rate of 52%. Similar incidence (11%) and mortality (54%) estimates for IPA were observed in the sensitivity analysis including severe cases requiring ICU support. Subgroup analysis by geographical location showed a similar IPA rate between European (10%) and non-European (11%) studies. The IPA rate in the subset of nine studies using the modified AspICU criteria was 13%. Most subgroup analyses showed ≥50% mortality in IPA patients. Several predictors for IPA susceptibility were identified, including male sex, smoking history, chronic lung disease, influenza A (H1N1), severe conditions requiring supportive therapy, corticosteroid use before admission, solid organ transplant and haematological malignancy. CONCLUSIONS: The IPA is common in individuals with severe influenza, and the prognosis is particularly poor. Influenza patients, especially those with high-risk factors, should be thoroughly screened for IPA.

The Extent of Aspergillosis in Critically Ill Patients With Severe Influenza Pneumonia: A Multicenter Cohort Study.

OBJECTIVES: To determine the frequency and prognosis of invasive pulmonary aspergillosis in critically ill patients with severe influenza pneumonia. DESIGN: Retrospective multicenter cohort study. SETTING: Five French ICUs. PATIENTS: Patients with influenza admitted to ICU between 2009 and 2018. MEASUREMENTS AND MAIN RESULTS: Of the 524 patients admitted for severe influenza diagnosed with a positive airway reverse-transcriptase polymerase chain reaction test, 450 (86%) required mechanical ventilation. A lower respiratory tract sample yielded with Aspergillus (Asp+) in 28 patients (5.3%). Ten patients (1.9%) were diagnosed with putative or proven invasive pulmonary aspergillosis, based on the validated AspICU algorithm. A multivariate model was built to identify independent risk factors for Aspergillus-positive pulmonary culture. Factors independently associated with Aspergillus-positive culture were liver cirrhosis (odds ratio = 6.7 [2.1-19.4]; p < 0.01), hematologic malignancy (odds ratio = 3.3 [1.2-8.5]; p = 0.02), Influenza A(H1N1)pdm09 subtype (odds ratio = 3.9 [1.6-9.1]; p < 0.01), and vasopressor requirement (odds ratio = 4.1 [1.6-12.7]; p < 0.01). In-hospital mortality of Asp+ patients was 36% versus 21% in patients without Aspergillus-positive pulmonary culture (p = 0.09). CONCLUSIONS: In this large retrospective multicenter cohort of critically ill patients, putative invasive pulmonary aspergillosis according to AspICU algorithm was a relatively rare complication of influenza. Patients at higher risk of Aspergillus pulmonary colonization included those with liver cirrhosis, hematologic malignancy, H1N1pdm09 influenza A virus, and requiring vasopressors. Our results provide additional data on the controversial association between severe influenza and invasive pulmonary aspergillosis. Reaching a consensual definition of invasive pulmonary aspergillosis becomes mandatory and confers further prospective research.

Invasive pulmonary aspergillosis in the COVID-19 era: An expected new entity.

OBJECTIVES: Information on the recently COVID-19-associated pulmonary aspergillosis (CAPA) entity is scarce. We describe eight CAPA patients, compare them to colonised ICU patients with coronavirus disease 2019 (COVID-19), and review the published literature from Western countries. METHODS: Prospective study (March to May, 2020) that included all COVID-19 patients admitted to a tertiary hospital. Modified AspICU and European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria were used. RESULTS: COVID-19-associated pulmonary aspergillosis was diagnosed in eight patients (3.3% of 239 ICU patients), mostly affected non-immunocompromised patients (75%) with severe acute respiratory distress syndrome (ARDS) receiving corticosteroids. Diagnosis was established after a median of 15 days under mechanical ventilation. Bronchoalveolar lavage was performed in two patients with positive Aspergillus fumigatus cultures and galactomannan (GM) index. Serum GM was positive in 4/8 (50%). Thoracic CT scan findings fulfilled EORTC/MSG criteria in one case. Isavuconazole was used in 4/8 cases. CAPA-related mortality was 100% (8/8). Compared with colonised patients, CAPA subjects were administered tocilizumab more often (100% vs. 40%, p = .04), underwent longer courses of antibacterial therapy (13 vs. 5 days, p = .008), and had a higher all-cause mortality (100% vs. 40%, p = .04). We reviewed 96 similar cases from recent publications: 59 probable CAPA (also putative according modified AspICU), 56 putative cases and 13 colonisations according AspICU algorithm; according EORTC/MSG six proven and two probable. Overall, mortality in the reviewed series was 56.3%. CONCLUSIONS: COVID-19-associated pulmonary aspergillosis must be considered a serious and potentially life-threatening complication in patients with severe COVID-19 receiving immunosuppressive treatment.

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

Although patients with severe immunodeficiency and hematological malignancies has been considered at highest risk for invasive fungal infection, patients with severe pneumonia due to influenza, and severe acute respiratory syndrome coronavirus (SARS-CoV) are also at a higher risk of developing invasive pulmonary aspergillosis (IPA). Recently, reports of IPA have also emerged among SARS-CoV-2 infected patients admitted to intensive care units (ICUs). Here, we report a fatal case of probable IPA in an acute myeloid leukemia patient co-infected with SARS-CoV-2 and complicated by acute respiratory distress syndrome (ARDS). Probable IPA is supported by multiple pulmonary nodules with ground glass opacities which indicate halo sign and positive serum galactomannan results. Screening studies are needed to evaluate the prevalence of IPA in immunocompromised patients infected with SARS-CoV-2. Consequently, testing for the presence of Aspergillus in lower respiratory secretions and galactomannan in consecutive serum samples of COVID-19 patients with timely and targeted antifungal therapy based on early clinical suspicion of IPA are highly recommended.

Invasive pulmonary aspergillosis in critically ill patients with hematological malignancies.

PURPOSE: Invasive pulmonary aspergillosis (IPA) is a dreadful event in patients with hematological malignancies (HM). Recent advances have standardized diagnostic, prophylactic and curative therapeutic strategies. We sought to assess whether these advances actually translate into improved survival in critically ill patients with acute respiratory failure and IPA. METHODS: This was a retrospective, multicenter study. Adult patients with HM, IPA, admitted to the ICU for acute respiratory failure over a 20-year period (January 1998-December 2017) were included. A cox regression model was used to identify variables independently associated with day-90 survival. RESULTS: Overall, 219 patients were included [138 (63%) men, median age 55 (IQR 44-64)]. Acute myeloid leukemia (30.1%) and non-Hodgkin lymphoma (22.8%) were the most frequent malignancies, and 53 (24.2%) were allogeneic stem cell recipients. Day-1 SOFA score was 9 [7-12]. Most patients presented with probable IPA, whereas 15 (7%) underwent lung biopsies or pleurocentesis and met criteria for proven IPA. Overall ICU and day-90 mortality were, respectively, 58.4% and 75.2% (80.4% if invasive mechanical ventilation) without any significant improvement over time. By multivariable analysis adjusted on day-1 SOFA score and ventilation strategies, voriconazole use (HR 0.49, CI 95 0.34-0.73, p < 0.001) and an ICU admission after 2010 (HR 0.67, 0.45-0.99, p = 0.042) were associated with increased survival, whereas a diffuse radiologic pattern (HR 2.07, CI 95 1.33-3.24, p = 0.001) and delayed admission to the ICU (HR 1.51, CI 95 1.05-2.16, p = 0.026) were independently associated with increased mortality. CONCLUSIONS: IPA is associated with high mortality rates in critically ill patients with acute respiratory failure. Routine voriconazole and prompt ICU admission are warranted.

Invasive aspergillosis in critically ill patients: An autopsy study.

Autopsy studies show that IA is among the most commonly missed diagnoses in critically ill patients. And, because of lack of unequivocal diagnostic criteria, a timely diagnosis remains challenging. We investigate the epidemiology of and the clinical risk factors for IA in critically ill patients. We conducted a retrospective, observational study of all consecutive ICU patients with evidence of IA in the postmortem examination. During the period of the study (25 years), 893 postmortem examinations were performed in the ICU. Twenty-five patients (2.8%) were diagnosed with IA in autopsy. Only ten (40%) were classified as IA ante-mortem, based on the initiation of antifungal treatment. The most common comorbid conditions were corticosteroid treatment (n = 14, 56%), chronic obstructive pulmonary disease (COPD) (n = 11, 44%), immunosuppression (n = 6, 24%) and haematological malignancy (n = 5, 20%). Twenty-three patients (92%) had three or more risk factors for IA. Critically ill patients with pulmonary infiltrates, treated with high doses intravenous corticosteroids (even for a short period of time), particularly COPD patients who developed worsening respiratory insufficiency despite appropriate treatment were at the highest risk of IA.

Invasive pulmonary aspergillosis in acute leukemia: a still frequent condition with a negative impact on the overall treatment outcome.

We evaluated the impact of invasive pulmonary aspergillosis (IPA) on epidemiology and outcome in acute leukemia (AL), analyzing all acute myeloid (AML) and acute lymphoblastic leukemia (ALL) consecutively admitted to our Institution during a 5-year period of observation. Only AML patients received anti-mold prophylaxis. Among 175 AL patients (136 AML/39 ALL), possible and proven/probable IPA were diagnosed in 28 (16%). Frequency of IPA was similar in AML (16.2%) and in ALL (15.4%). Two-year overall survival (OS) was significantly affected by IPA (no IPA: 69.8% vs IPA: 31.7% p = .002). OS was similar in patients with proven/probable (28.2%) and possible IPA (36.4%) (p = .003 and .065, respectively). When censoring patients at transplant, IPA still affected 2-year survival (49.6% vs 79.2%, p = .02), but only proven/probable IPA was associated with lower survival (34.7%, p = .0003). IPA negatively impacts on long-term survival of leukemia patients; antifungal prophylaxis should be adopted also during induction in ALL and in AML beyond induction therapy.

Utility of CT assessment in hematology patients with invasive aspergillosis: a post-hoc analysis of phase 3 data.

BACKGROUND: Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected. METHODS: This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan. RESULTS: Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had 'confirmed' proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had 'non-confirmed' invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813-21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA. CONCLUSIONS: These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation. TRIAL REGISTRATION: NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007).

Voriconazole Resistance and Mortality in Invasive Aspergillosis: A Multicenter Retrospective Cohort Study.

BACKGROUND: Triazole resistance is an increasing problem in invasive aspergillosis (IA). Small case series show mortality rates of 50%-100% in patients infected with a triazole-resistant Aspergillus fumigatus, but a direct comparison with triazole-susceptible IA is lacking. METHODS: A 5-year retrospective cohort study (2011-2015) was conducted to compare mortality in patients with voriconazole-susceptible and voriconazole-resistant IA. Aspergillus fumigatus culture-positive patients were investigated to identify patients with proven, probable, and putative IA. Clinical characteristics, day 42 and day 90 mortality, triazole-resistance profiles, and antifungal treatments were investigated. RESULTS: Of 196 patients with IA, 37 (19%) harbored a voriconazole-resistant infection. Hematological malignancy was the underlying disease in 103 (53%) patients, and 154 (79%) patients were started on voriconazole. Compared with voriconazole-susceptible cases, voriconazole resistance was associated with an increase in overall mortality of 21% on day 42 (49% vs 28%; P = .017) and 25% on day 90 (62% vs 37%; P = .0038). In non-intensive care unit patients, a 19% lower survival rate was observed in voriconazole-resistant cases at day 42 (P = .045). The mortality in patients who received appropriate initial voriconazole therapy was 24% compared with 47% in those who received inappropriate therapy (P = .016), despite switching to appropriate antifungal therapy after a median of 10 days. CONCLUSIONS: Voriconazole resistance was associated with an excess overall mortality of 21% at day 42 and 25% at day 90 in patients with IA. A delay in the initiation of appropriate antifungal therapy was associated with increased overall mortality.

Treating invasive aspergillosis in patients with hematologic malignancy: diagnostic-driven approach versus empiric therapies.

BACKGROUND: Early antifungal therapy for invasive aspergillosis (IA) has been associated with improved outcome. Traditionally, of empiric antifungal therapy has been used for clinically suspected IA. We compared outcomes of patients with hematologic malignancy and IA who were treated with voriconazole using the diagnostic driven DDA (DDA-Vori) that includes galactomannan testing vs. empiric therapy with a non-voriconazole-containing regimen (EMP-non-Vori) or empiric therapy with voriconazole (EMP-Vori). METHODS: We retrospectively reviewed the medical records of 342 hematologic malignancy patients diagnosed with proven, or probable IA between July 1993 and February 2016 at our medical center who received at least 7 days of DDA-Vori, EMP-Vori, or EMP-non-Vori. Outcome assessment included response to therapy (clinical and radiographic), all-cause mortality, and IA-attributable mortality. RESULTS: By multivariate analysis, factors predictive of a favorable response included localized/sinus IA vs. disseminated/pulmonary IA (p <  0.0001), not receiving white blood cell transfusion (p <  0.01), and DDA-Vori vs. EMP-non-Vori (p < 0.0001). In contrast, predictors of mortality within 6 weeks of initiating IA therapy included disseminated/pulmonary infection vs. localized/sinus IA (p < 0.01), not undergoing stem cell transplantation within 1 year before IA (p = 0.01), and EMP-non-Vori vs. DDA-Vori (p < 0.001). CONCLUSIONS: DDA-Vori was associated with better outcome (response and survival) compared with EMP-non-Vori and with equivalent outcome to EMP-Vori in hematologic malignancy patients. These outcomes associated with the implementation of DDA could lead to a reduction in the unnecessary costs and adverse events associated with the widespread use of empiric therapy.

Invasive pulmonary aspergillosis in patients with solid tumours: risk factors and predictors of clinical outcomes.

BACKGROUND: The characteristics and management of invasive pulmonary aspergillosis (IPA) in patients with hematologic malignancies are well known, but IPA in patients with solid tumours is not well described. METHODS: We retrospectively reviewed all Aspergillus-positive cultures at a tertiary cancer center during 2004-2017. We identified 101 patients with IPA and solid tumours. We analyzed the association between clinical features and treatment and 12-week mortality and response to antifungal therapy. RESULTS: Fifty-one patients had lung cancer, 77 had underlying lung disease, 47 received chest radiation and 33 had chronic obstructive pulmonary disease. Aspergillus fumigatus was the most common type isolated (71%); 68 patients (70%) were treated with voriconazole monotherapy. Independent risk factors for 12-week mortality included receiving steroids within 30 days of diagnosis (hazard ratio 2.2, 95% confidence interval [CI]: 1.1-4.6; p = .03) and chest radiotherapy (hazard ratio 2.6, 95% CI: 1.2-5.5; p = .01). In multivariate analysis, a positive fungal stain was associated with lower odds of a successful response (odds ratio 0.2; 95% CI: 0.05-0.75; p = .02), whereas voriconazole treatment was associated with higher odds (odds ratio 10.1; 95% CI: 2.1-48.5; p < .01). CONCLUSIONS: IPA should be considered in patients with solid tumours, particularly those with underlying lung disease. Key messages Invasive pulmonary aspergillosis should be considered in patients with solid tumours, particularly those with underlying lung disease, lung cancer and those who received chest radiotherapy. Most of the patients with invasive pulmonary aspergillosis and solid tumours presented with nonspecific symptoms and signs as well as nonspecific CT findings. Unlike patients with hematologic malignancies, fever and hemoptysis were not predominant symptoms and the classical halo sign and the air-crescent sign were not described. Independent risk factors for 12-week mortality included receiving steroids within 30 days of diagnosis and chest radiotherapy. In multivariate analysis, a positive fungal stain was associated with lower odds of a successful response to antifungal therapy, whereas voriconazole treatment was associated with higher odds.

Clinical risk factors for invasive aspergillosis in lung transplant recipients: Results of an international cohort study.

BACKGROUND: Invasive aspergillosis (IA) is a frequent complication in lung transplant recipients (LTRs). Clinical risk factors for IA have not been fully characterized, especially in the era of extensive anti-fungal prophylaxis. The primary objective of this study was to evaluate the clinical risk factors associated with IA in LTRs. The secondary objective was to assess the mortality in LTRs who had at least 1 episode of IA compared with LTRs who never had experienced IA. METHODS: We conducted an international, multicenter, retrospective cohort study of 900 consecutive adults who received lung transplants between 2005 and 2008 with 4years of follow-up. Risk factors associated with IA were identified using univariate and multiple regression Cox proportional hazards models. RESULTS: Anti-fungal prophylaxis was administered to 61.7% (555 of 900) of patients, and 79 patients developed 115 episodes of IA. The rate to development of the first episode was 29.6 per 1,000 person-years. Aspergillus fumigatus was the most common species isolated (63% [72 of 115 episodes]). Through multivariate analysis, significant risk factors identified for IA development were single lung transplant (hazard ratio, 1.84; 95% confidence interval, 1.09-3.10; p = 0.02,) and colonization with Aspergillus at 1 year post-transplantation (hazard ratio, 2.11; 95% confidence interval, 1.28-3.49; p = 0.003,). Cystic fibrosis, pre-transplant colonization with Aspergillus spp, and use of anti-fungal prophylaxis were not significantly associated with the development of IA. Time-dependent analysis showed IA was associated with higher mortality rates. CONCLUSION: Incidence of IA remains high in LTRs. Single-lung transplant and airway colonization with Aspergillus spp. within 1 year post-transplant were significantly associated with IA.

Values of radiological examinations for the diagnosis and prognosis of invasive bronchial-pulmonary aspergillosis in critically ill patients with chronic obstructive pulmonary diseases.

INTRODUCTION: The important role of radiological examinations of invasive pulmonary aspergillosis (IPA) in patients with neutropenia has been well studied; however, little is known about IPA in critically ill chronic obstructive pulmonary disease (COPD) patients. OBJECTIVES: To evaluate the value of radiological examinations in the diagnosis and prognosis of invasive bronchial-pulmonary aspergillosis (IBPA) in critically ill COPD patients. METHODS: We included 61 critically ill COPD patients in the intensive care unit (ICU) in a retrospective, single-center cohort study. RESULTS: All of the patients were classified as IBPA group (n = 21) or non-IBPA group (n = 40). The chest computed tomography (CT) image analysis showed that the IBPA group had the highest percent of patchiness (76.2%), followed by multiple nodules (33.3%), angio-invasive patterns (including halo sign, wedge consolidation and air-crescent sign/cavity with a relatively low percent of 19%, 19% and 28.5%, respectively), and the multiple nodules that were distributed along the airway provided the most specific image, with the highest specificity of 92.5%. Compared to the survivors in the IBPA group, non-surviving patients had a higher percent of large consolidation (0% vs. 45.5%, P = .035). When the new effusions appeared on a chest x-ray (CXR), the creatinine (140.4 µmol/L vs. 64.0 µmol/L, P = .010) and PaO2 /FiO2 (188 mm Hg vs. 222 mm Hg, P = .034) rate deteriorated. CONCLUSIONS: Multiple nodules that were distributed along with broncho-vascular bundles were relatively common and specific in critically ill COPD patients with IBPA. Deteriorated CXR combined with specific laboratory examinations, even when appropriate antibiotics were used, could indicate a diagnosis of IBPA. Large consolidations might be considered as poor prognostic indicators.

Clinical characteristics and outcome of invasive fungal infections in pediatric acute myeloid leukemia patients in a medical center in Taiwan.

BACKGROUND: Invasive fungal infection (IFI) causes significant morbidity and mortality in patients with hematological malignancies, especially those with acute myeloid leukemia (AML), recurrent acute leukemia, high-risk acute lymphoblastic leukemia, and after allogeneic hematopoietic stem cell transplantation. The study aimed to investigate the clinical characteristics and outcome of IFIs in pediatric AML patients in a medical center in Taiwan. METHODS: We performed retrospective chart reviews. We enrolled pediatric AML patients who were admitted to National Taiwan University Hospital between January 2005 and December 2014. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycosis Study Group 2008 consensus criteria. RESULTS: In total, 78 patients were included for analysis. Twenty two episodes of IFIs were identified in 16 patients. The incidence for IFIs was 20.5% (16/78), and no specific trend of increase or decrease was observed through the study period (p=0.374). Candida species caused the majority (59.1%) of IFIs. Prolonged neutropenia and elevated alanine aminotransferase and creatinine values were factors associated with IFIs (p<0.001, p<0.001, and p=0.001, respectively). Patients with endotracheal intubation or inotropes usage had a higher probability of developing IFIs (p<0.001 and p=0.001, respectively). The overall mortality of IFIs was 53% (8/15) over 10 years, and patients with pulmonary aspergillosis had the highest mortality (80%). CONCLUSION: IFIs continue to pose significant morbidity and mortality in pediatric AML patients, and patients with other hematology-oncology cancers. Recognition of factors associated with IFIs may help us early identify IFIs and promptly initiate antifungal therapy.

Complete surgical resection and short-term survival in acute invasive fungal rhinosinusitis.

BACKGROUND: Acute invasive fungal rhinosinusitis (AIFR) is a fulminant fungal infection seen in patients who are immunocompromised. Due to its rarity, there is little evidence regarding the appropriate antifungal treatment regimen, especially the degree of surgical intervention. OBJECTIVE: To assess factors that impact short-term survival in AIFR as defined by survival to hospital discharge and to develop a staging system to predict survival and complete surgical resection. METHODS: Fifty-four patients with histopathologically diagnosed AIFR who met inclusion criteria were identified between 1984 and 2014. Patient characteristics, disease extent, treatment modality, and short-term survival data were collected. Univariate analysis was performed to assess for factors associated with survival and increased likelihood of surgical resection. RESULTS: Of 52 patients with adequate documentation, 36 (69.2%) survived their hospital stay. Complete surgical resection was the only factor associated with improved survival (survival, 95.5%; p < 0.01). A surgical staging system was proposed to guide probability of complete resection and overall prognosis, with stage I disease limited to the nasal cavity, stage II involving the paranasal sinuses, stage III involving the orbit, and stage IV with skull base or intracranial extension. The χ2 analyses showed a decreased likelihood of complete surgical resection with stage III or IV disease compared with stage I (resection, 90.9%) (stage III resection, 37.5% [p = 0.01]; stage IV resection, 16.7% [p = 0.002]). There was a decreased likelihood of survival associated with increasing disease stage compared with stage I (survival, 100%) (stage II survival, 60% [p = 0.009]; stage III survival, 62.5% [p = 0.02]; stage IV survival, 54.6%, [p = 0.006]). CONCLUSION: Although further studies are needed to define specific treatment protocols, analysis of these data indicated that endoscopic sinus surgery with the goal of complete surgical resection may provide the best survival outcomes in select patients when complete surgical resection can be performed. Our staging system represents the first attempt to predict surgical success and prognosis in patients with AIFR.

Changes in In Vitro Susceptibility Patterns of Aspergillus to Triazoles and Correlation With Aspergillosis Outcome in a Tertiary Care Cancer Center, 1999-2015.

BACKGROUND: Azole-resistant aspergillosis in high-risk patients with hematological malignancy or hematopoietic stem cell transplantation (HSCT) is a cause of concern. METHODS: We examined changes over time in triazole minimum inhibitory concentrations (MICs) of 290 sequential Aspergillus isolates recovered from respiratory sources during 1999-2002 (before introduction of the Aspergillus-potent triazoles voriconazole and posaconazole) and 2003-2015 at MD Anderson Cancer Center. We also tested for polymorphisms in ergosterol biosynthetic genes (cyp51A, erg3C, erg1) in the 37 Aspergillus fumigatus isolates isolated from both periods that had non-wild-type (WT) MICs. For the 107 patients with hematologic cancer and/or HSCT with invasive pulmonary aspergillosis, we correlated in vitro susceptibility with 42-day mortality. RESULTS: Non-WT MICs were found in 37 (13%) isolates and was only low level (MIC <8 mg/L) in all isolates. Higher-triazole MICs were more frequent in the second period and were Aspergillus-species specific, and only encountered in A. fumigatus. No polymorphisms in cyp51A, erg3C, erg1 genes were identified. There was no correlation between in vitro MICs with 42-day mortality in patients with invasive pulmonary aspergillosis, irrespective of antifungal treatment. Asian race (odds ratio [OR], 20.9; 95% confidence interval [CI], 2.5-173.5; P = .005) and azole exposure in the prior 3 months (OR, 9.6; 95% CI, 1.9-48.5; P = .006) were associated with azole resistance. CONCLUSIONS: Non-WT azole MICs in Aspergillus are increasing and this is associated with prior azole exposure in patients with hematologic cancer or HSCT. However, no correlation of MIC with outcome of aspergillosis was found in our patient cohort.

A retrospective study of the epidemiology and clinical manifestation of invasive aspergillosis in a major tertiary care hospital in Bahrain.

Limited data are available on the epidemiology, clinical manifestations and outcomes of patients with invasive aspergillosis in Bahrain. This study was conducted retrospectively to determine the epidemiology of invasive aspergillosis and its risk factors, clinical presentation, underlying conditions, and outcomes over the past five years in a major hospital. The medical records of patients with positive Aspergillus cultures admitted to a major tertiary care hospital in Bahrain during 2009-2013 were reviewed. Cases were classified according to (1) the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (MSG) criteria (proven, probable, possible IA or not classifiable) and (2) "validated" criteria to distinguish Aspergillus colonization from IA (putative or proven IA). Demographic, microbiologic and diagnostic data were collected, and outcomes were recorded. A total of 60 patients were included, of whom 44 were colonized (73.3%), and 16 had probable IA (26.7%); no proven or possible IA cases were identified according to the EORTC/Mycoses Study Group (MSG) criteria. In comparison, with the alternative "validated" criteria, 32 were colonized (53.3%), 28 had putative IA (46.7%), and none had proven IA (0%). The lung was the most common site of infection, and Aspergillus fumigatus was the most commonly isolated species (53%). Mortality was 25% among colonized patients, 44% in probable cases and 32% in those with putative IA. All patients were immunocompromised or had one or more predisposing factors. Independent risk factors for death among patients with IA included older age, history of mechanical ventilation, renal replacement therapy and higher sequential organ failure assessment scores at diagnosis.