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.

A review of significance of Aspergillus detection in airways of ICU COVID-19 patients.

It is now well known that patients with SARS-CoV-2 infection admitted in ICU and mechanically ventilated are at risk of developing invasive pulmonary aspergillosis (IPA). Nevertheless, symptomatology of IPA is often atypical in mechanically ventilated patients, and radiological aspects in SARS-CoV-2 pneumonia and IPA are difficult to differentiate. In this context, the significance of the presence of Aspergillus in airway specimens (detected by culture, galactomannan antigen or specific PCR) remains to be fully understood. To decipher the relevance of the detection of Aspergillus, we performed a comprehensive review of all published cases of respiratory Aspergillus colonisation and IPA in COVID-19 patients. The comparison of patients receiving or not antifungal treatment allowed us to highlight the most important criteria for the decision to treat. The comparison of surviving and non-surviving patients made it possible to unveil criteria associated with mortality that should be taken into account in the treatment decision.

Proven COVID-19-associated pulmonary aspergillosis in patients with severe respiratory failure.

BACKGROUND: An increasing number of reports have described the COVID-19-associated pulmonary aspergillosis (CAPA) as being a further contributing factor to mortality. Based on a recent consensus statement supported by international medical mycology societies, it has been proposed to define CAPA as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Considering current challenges associated with proven diagnoses, there is pressing need to study the epidemiology of proven CAPA. METHODS: We report the incidence of histologically diagnosed CAPA in a series of 45 consecutive COVID-19 laboratory-confirmed autopsies, performed at Padova University Hospital during the first and second wave of the pandemic. Clinical data, laboratory data and radiological features were also collected for each case. RESULTS: Proven CAPA was detected in 9 (20%) cases, mainly in the second wave of the pandemic (7/17 vs. 2/28 of the first wave). The population of CAPA patients consisted of seven males and two females, with a median age of 74 years. Seven patients were admitted to the intensive care unit. All patients had at least two comorbidities, and concomitant lung diseases were detected in three cases. CONCLUSION: We found a high frequency of proven CAPA among patients with severe COVID-19 thus confirming at least in part the alarming epidemiological data of this important complication recently reported as probable CAPA.

Mortality in critically ill patients with coronavirus disease 2019-associated pulmonary aspergillosis: A systematic review and meta-analysis.

Reports of COVID-19 associated pulmonary aspergillosis (CAPA) are rising, but the associated mortality and factors affecting it are not well-characterised. We performed a systematic review including 20 peer-reviewed English language studies reporting mortality in CAPA published till 18 February 2021from PubMed, Ovid SP, Web of Science, Embase and CINHAL. The pooled mortality in CAPA was 51.2% (95% CI: 43.1-61.1, I2  = 38%). The leave one out sensitivity analysis and influential case diagnostics revealed one outlier and its exclusion resulted in a mortality estimate of 54% (95% CI: 45-62). Higher odds of mortality: 2.83 (95% CI: 1.8-4.5) were seen in CAPA compared to controls. No significant difference in various subgroups according to the country of study, the continent of study, income category of country and quality of the included study was seen. None of the host risk factors, mycological test results, therapy for COVID-19 and antifungal therapy affected mortality. Thus, patients with CAPA have a high probability of mortality and early diagnosis with prompt therapy must be ensured to optimally manage these patients. However, more prospective studies with global and multi-centre coordination may help to address CAPA in a better way.

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

COVID-19-associated pulmonary aspergillosis (CAPA) has been reported worldwide. However, basic epidemiological characteristics have not been well established. In this systematic review and meta-analysis, we aimed to determine the incidence and mortality of CAPA in critically ill patients with COVID-19 to improve guidance on surveillance and prognostication. Observational studies reporting COVID-19-associated pulmonary aspergillosis were searched with PubMed and Embase databases, followed by an additional manual search in April 2021. We performed a one-group meta-analysis on the incidence and mortality of CAPA using a random-effect model. We identified 28 observational studies with a total of 3148 patients to be included in the meta-analysis. Among the 28 studies, 23 were conducted in Europe, two in Mexico and one each in China, Pakistan and the United States. Routine screening for secondary fungal infection was employed in 13 studies. The modified AspICU algorithm was utilised in 15 studies and was the most commonly used case definition and diagnostic algorithm for pulmonary aspergillosis. The incidence and mortality of CAPA in the ICU were estimated to be 10.2% (95% CI, 8.0-12.5; I2  = 82.0%) and 54.9% (95% CI, 45.6-64.2; I2  = 62.7%), respectively. In conclusion, our estimates may be utilised as a basis for surveillance of CAPA and prognostication in the ICU. Large, prospective cohort studies based on the new case definitions of CAPA are warranted to validate our estimates.

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.

Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial.

BACKGROUND: Voriconazole has been recommended as primary treatment for patients with invasive aspergillosis. Intravenous and tablet formulations of posaconazole that have improved systemic absorption could be an effective alternative to voriconazole. We aimed to assess non-inferiority of posaconazole to voriconazole for the primary treatment of invasive aspergillosis. METHODS: We did a randomised, prospective, double-blind, double-dummy, controlled trial comparing posaconazole (intravenous or oral posaconazole 300 mg twice on day 1, followed by 300 mg once a day for days 2-84) with voriconazole (6 mg/kg intravenous or 300 mg oral twice on day 1 followed by 4 mg/kg intravenously or 200 mg orally twice a day for days 2-84) for 12 weeks or less in the primary treatment of invasive aspergillosis. Participants were from 91 study sites in 26 countries, were aged 13 years or older, weighed at least 40 kg, and met criteria for proven, probable, or possible fungal disease. Participants were randomly assigned (1:1) via a computer-generated randomisation schedule with stratification by risk status. The primary endpoint was cumulative all-cause mortality up until day 42 in the intention-to-treat (ITT) population (defined as randomly assigned participants who received ≥1 dose of study drug), with a 10% non-inferiority margin. The ITT population was also evaluated for safety. This study is registered with ClinicalTrials.gov, NCT01782131, and EudraCT, 2011-003938-14. FINDINGS: Between Oct 25, 2013, and Sept 10, 2019, of 653 individuals assessed for eligibility, 575 ITT participants were randomly assigned and received one or more doses of study drug (n=288 [50%] posaconazole, n=287 [50%] voriconazole). Mortality up until day 42 was 15% (44 of 288) in the posaconazole group and 21% (59 of 287) in the voriconazole group (treatment difference -5·3% [95% CI -11·6 to 1·0]; p<0·0001). Mortality up until day 42 in the full-analysis-set subpopulation (ITT participants with proven or probable invasive aspergillosis) supported this conclusion: 31 (19%) of 163 participants in the posaconazole group and 32 (19%) of 171 participants in the voriconazole group (treatment difference 0·3% [95% CI -8·2 to 8·8]). The most frequently reported treatment-related adverse events (incidence >3%) were increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT), nausea, hypokalaemia, and vomiting in the posaconazole group and increased ALT, AST, or alkaline phosphatase, hallucination, increased γ-glutamyltransferase peptidase, nausea, and blurred vision in the voriconazole group. The overall incidence of treatment-related adverse event rates in the ITT population was 30% for posaconazole and 40% for voriconazole (treatment difference -10·2% [95% CI -17·9 to -2·4]). INTERPRETATION: Posaconazole was non-inferior to voriconazole for all-cause mortality up until day 42 in participants with invasive aspergillosis. Posaconazole was well tolerated, and participants had fewer treatment-related adverse events than in the voriconazole group. This study supports the use of posaconazole as a first-line treatment for the condition. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.

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 immunocompetent patients hospitalised with influenza A-related pneumonia: a multicenter retrospective study.

BACKGROUND: Increasing cases of pulmonary aspergillosis (IPA) in immunocompetent patients with severe influenza have been reported. Howevere, the risk factors for occurence and death are largely unknown. METHODS: Data of hospitalised patients with influenza A-related pneumonia (FluA-p) obtained from five teaching hospitals from 2031 to 2018, were reviewed. Univariate and multivariate logistical regression analyses were performed to determine the risk factors involved in the acquisition and 60-day mortality in IPA patients. RESULTS: Of the 693 FluA-p patients included in the study, 3.0% (21/693) were IPA patients with a 60-day mortality of 42.9% (9/21). Adjusted for confounders, a Cox proportional hazard model showed that IPA was associated with increased risk for 60-day mortality [hazard ratio (HR) 4.336, 95% confidence interval (CI) 1.191-15.784, p = 0.026] in FluA-p patients. A multivariate logistic regression model confirmed that age (odd ratio (OR) 1.147, 95% CI 1.048-1.225, p = 0.003), systemic corticosteroids use before IPA diagnosis (OR 33.773, 95% CI 5.681-76.764, p <  0.001), leukocytes > 10 × 109/L (OR 1.988, 95% CI 1.028-6.454, p = 0.029) and lymphocytes < 0.8 × 109/L on admission (OR 34.813, 95% CI 1.676-73.006, p = 0.022), were related with the acquisition of IPA. Early neuraminidase inhibitor use (OR 0.290, 95% CI 0.002-0.584, p = 0.021) was associated with a decreased risk for a 60-day mortality in IPA patients. CONCLUSIONS: Our results showed that IPA worsen the clinical outcomes of FluA-p patients. The risk factors for the acquisition and death were helpful for the clinicians in preventing and treating IPA.

Influenza-associated aspergillosis in critically-ill patients-a retrospective bicentric cohort study.

Influenza was recently reported as a risk factor for invasive aspergillosis (IA). We aimed to describe prognostic factors for influenza-associated IA (IAA) and poor outcome and mortality in critically ill patients in Switzerland. All adults with confirmed influenza admitted to the ICU at two Swiss tertiary care centres during the 2017/2018 influenza season were retrospectively evaluated. IAA was defined by clinical, mycological and radiological criteria: a positive galactomannan in bronchoalveolar lavage or histopathological or cultural evidence in respiratory specimens of Aspergillus spp., any radiological infiltrate and a compatible clinical presentation. Poor outcome was defined as a composite of in-hospital mortality, ICU length of stay (LOS), invasive ventilation for > 7 days or extracorporeal membrane oxygenation. Of 81 patients with influenza in the ICU, 9 (11%) were diagnosed with IAA. All patients with IAA had poor outcome compared to 26 (36%) patients without IAA (p < 0.001). Median ICU-LOS and mortality were 17 vs. 3 days (p < 0.01) and 3/9 (33%) vs. 13/72 (18%; p = 0.37) in patients with vs. without IAA, respectively. Patients with IAA had significantly longer durations of antibiotic therapy, vasoactive support and mechanical ventilation. Aspergillus was the most common respiratory co-pathogen (9/40, 22%) followed by classical bacterial co-pathogens. IAA was not associated with classical risk factors. Aspergillus is a common superinfection in critically ill influenza patients associated with poor outcome and longer duration of organ supportive therapies. Given the absence of classical risk factors for aspergillosis, greater awareness is necessary, particularly in those requiring organ supportive therapies.

Risk factors for development and mortality of invasive pulmonary Aspergillosis in kidney transplantation recipients.

Invasive pulmonary aspergillosis (IPA) is a high mortality opportunistic infection among kidney transplant recipients. This study assessed the risk factors and outcomes of IPA after KT. A retrospective study was conducted at a tertiary-care referral hospital in Korea. Electronic medical records of patients diagnosed with IPA after KT between February 1995 and March 2015 were reviewed. The control patients comprised two patients who received KT before and after each IPA case. Twenty-six cases were diagnosed with IPA among 1963 recipients at a median of 58 years old. The most common cause of end-stage renal disease was diabetic nephropathy. The median time to diagnosis was 161 days. Delayed graft function was associated with the development of IPA. The overall 12-week mortality rate of IPA was 57.5%. Serum GM level ≥ 2 and BAL GM level ≥ 5 were associated with 12-week mortality in the Kaplan-Meier survival analyses. Approximately half of IPA in KT recipients developed during the late posttransplant period (> 6 months), especially after treatment for acute rejection. Careful monitoring for IPA is required in patients with delayed graft function, DM, and who received rejection therapy. Higher serum and BAL GM were associated with 12-week mortality.

Late Onset Invasive Pulmonary Aspergillosis in Lung Transplant Recipients in the Setting of a Targeted Prophylaxis/Preemptive Antifungal Therapy Strategy.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). It is unclear how a targeted prophylaxis/ preemptive antifungal therapy strategy impacts the incidence of IPA beyond the first-year posttransplant. METHODS: This is a retrospective cohort of LTRs from January 2010 to December 2014. We included all LTRs who survived beyond the first year and followed them until death or 4 years postoperatively. Incidence of probable/proven IPA and Aspergillus colonization were assessed as per International Society for Heart and Lung Transplantation (ISHLT) criteria. Patients with risk factors, positive Aspergillus cultures, or galactomannan (GM) received targeted prophylaxis/preemptive therapy within the first-year posttransplant. RESULTS: During the study period, 350 consecutive LTRs underwent 1078 bronchoscopies. Positive bronchoalveolar lavage for GM or Aspergillus cultures was reported for 15% (52/350) of LTRs between 2 and 4 years after transplantation. Among them, the median time to positive Aspergillus culture or GM positivity was 703 days (interquartile range, 529-754 d). The incidence rate of IPA and Aspergillus colonization was 30 of 1000 patient-y, and 63 of 1000 patient-y, respectively. The mortality rate was significantly higher in patients with IPA than without IPA (107/1000 patient-years versus 18/1000 patient-years; P < 0.0001). Rate of first-year colonization and IPA was 33% and 9%, respectively. Among the 201 patients who had a negative bronchoscopy during the first year posttransplant, only 6 (3%) developed IPA during the follow-up. CONCLUSIONS: A targeted prophylaxis/preemptive therapy strategy within the first-year posttransplant resulted in 4% incidence of IPA at 4-years after transplantation. However, IPA was associated with higher mortality.

Invasive Pulmonary Aspergillosis in Nonimmunocompromised Hosts.

Invasive pulmonary aspergillosis (IPA) is a fungal infection that is the hallmark of severe cellular or complex immune alterations. Evidence that IPA can occur in nonimmunocompromised hosts is increasing. Actually, up to 1% of general intensive care unit (ICU) patients present positive samples with Aspergillus spp. Both colonization and invasive disease are associated with poor outcome. Unexpected IPA has also been reported in approximately 1% of critically ill patients who underwent postmortem biopsies. In nonimmunocompromised patients with acute respiratory distress syndrome (ARDS), IPA prevalence can reach up to 15% of patients in both clinical and autopsy studies. Factors associated with IPA in nonimmunocompromised critically ill hosts include short and long courses of steroids, broad antibiotic therapy, chronic obstructive pulmonary disease, ARDS, liver failure, and the severity of organ dysfunctions.This review aims to appraise the prevalence of IPA in nonimmunocompromised hosts, address diagnostic challenges, and outcomes.

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 pulmonary aspergillosis in heart transplant recipients: Is mortality decreasing?

INTRODUCTION: Infection remains a major complication among heart transplant (HT) recipients, causing approximately 20% of deaths in the first year after transplantation. In this population, Aspergillus spp. can have various clinical presentations including invasive pulmonary aspergillosis (IPA), with high mortality (53-78%). OBJECTIVES: To establish the characteristics of IPA infection in HT recipients and their outcomes in our center. METHODS: Among 328 HTs performed in our center between 1998 and 2016, we identified five cases of IPA. Patient medical records were examined and clinical variables were extracted. RESULTS: All cases were male, and mean age was 62 years. The most common indication for HT was non-ischemic dilated cardiomyopathy. Productive cough was reported as the main symptom. The radiological assessment was based on chest X-ray and chest computed tomography. The most commonly reported radiographic abnormality was multiple nodular opacities in both techniques. Bronchoscopy was performed in all patients and Aspergillus fumigatus was isolated in four cases on bronchoalveolar lavage culture. Treatment included amphotericin in four patients, subsequently changed to voriconazole in three, and posaconazole in one patient, with total treatment lasting an average of 12 months. Neutropenia was found in only one patient, renal failure was observed in two patients, and concurrent cytomegalovirus infection in three patients. All patients were alive after a mean follow-up of 18 months. CONCLUSIONS: IPA is a potentially lethal complication after HT. Early diagnosis and prompt initiation of aggressive treatment are the cornerstone of better survival.

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.

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).