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.

TLR7 Expression Aggravates Invasive Pulmonary Aspergillosis by Suppressing Anti-Aspergillus Immunity of Macrophages.

Toll-like receptors (TLRs) play a critical role in early immune recognition of Aspergillus, which can regulate host defense during invasive pulmonary Aspergillosis (IPA). However, the role of TLR7 in the pathogenesis of IPA remains unknown. In this study, an in vivo model of IPA was established to investigate the contribution of TLR7 to host anti-Aspergillus immunity upon invasive pulmonary Aspergillus fumigatus infection. The effects of TLR7 on phagocytosis and killing capacities of A. fumigatus by macrophages and neutrophils were investigated in vitro We found that TLR7 knockout mice exhibited lower lung inflammatory response and tissue injury, higher fungal clearance, and greater survival in an in vivo model of IPA compared with wild-type mice. TLR7 activation by R837 ligand led to wild-type mice being more susceptible to invasive pulmonary Aspergillus fumigatus infection. Macrophages, but not neutrophils, were required for the protection against IPA observed in TLR7 knockout mice. Mechanistically, TLR7 impaired phagocytosis and killing of A. fumigatus by macrophages but not neutrophils. Together, these data identify TLR7 as an important negative regulator of anti-Aspergillus innate immunity in IPA, and we propose that targeting TLR7 will be beneficial in the treatment of IPA.

The Metabolic Cytokine Adiponectin Inhibits Inflammatory Lung Pathology in Invasive Aspergillosis.

Systemic immunity and metabolism are coregulated by soluble factors, including the insulin-regulating adipose tissue cytokine adiponectin. How these factors impact detrimental inflammatory responses during fungal infection remains unknown. In this study, we observed that mortality, fungal burden, and tissue histopathology were increased in adiponectin-deficient mice in a neutropenic model of invasive aspergillosis. Lung RNA sequencing, quantitative RT-PCR, and subsequent pathway analysis demonstrated activation of inflammatory cytokine pathways with upstream regulation by IL-1 and TNF in adiponectin-deficient mice with decreased/inhibited anti-inflammatory genes/pathways, suggesting broad cytokine-mediated pathology along with ineffective fungal clearance. Quantitative RT-PCR analysis confirmed increased transcription of IL-1a, IL-6, IL-12b, IL-17A/F, and TNF in adiponectin-deficient mice at early time points postinfection, with a specific increase in intracellular TNF in alveolar macrophages. Although eosinophil recruitment and activation were increased in adiponectin-deficient mice, mortality was delayed, but not decreased, in mice deficient in both adiponectin and eosinophils. Interestingly, neutrophil depletion was required for increased inflammation in adiponectin-deficient mice in response to swollen/fixed conidia, suggesting that immune suppression enhances detrimental inflammation, whereas invasive fungal growth is dispensable. Our results suggest that adiponectin inhibits excessive lung inflammation in invasive aspergillosis. Our study has therefore identified the adiponectin pathway as a potential source for novel therapeutics in immune-compromised patients with detrimental immunity to invasive fungal infection.

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.

Aspergillus fumigatus conidial metalloprotease Mep1p cleaves host complement proteins.

Innate immunity in animals including humans encompasses the complement system, which is considered an important host defense mechanism against Aspergillus fumigatus, one of the most ubiquitous opportunistic human fungal pathogens. Previously, it has been shown that the alkaline protease Alp1p secreted from A. fumigatus mycelia degrades the complement components C3, C4, and C5. However, it remains unclear how the fungal spores (i.e. conidia) defend themselves against the activities of the complement system immediately after inhalation into the lung. Here, we show that A. fumigatus conidia contain a metalloprotease Mep1p, which is released upon conidial contact with collagen and inactivates all three complement pathways. In particular, Mep1p efficiently inactivated the major complement components C3, C4, and C5 and their activation products (C3a, C4a, and C5a) as well as the pattern-recognition molecules MBL and ficolin-1, either by directly cleaving them or by cleaving them to a form that is further broken down by other proteases of the complement system. Moreover, incubation of Mep1p with human serum significantly inhibited the complement hemolytic activity and conidial opsonization by C3b and their subsequent phagocytosis by macrophages. Together, these results indicate that Mep1p associated with and released from A. fumigatus conidia likely facilitates early immune evasion by disarming the complement defense in the human host.

Diagnostic work up to assess early response indicators in invasive pulmonary aspergillosis in adult patients with haematologic malignancies.

In immunocompromised patients with acute leukaemia as well as in allogeneic hematopoietic stem cell transplant patients, pulmonary lesions are commonly seen. Existing guidelines provide useful algorithms for diagnostic procedures and treatment options, but they do not give recommendations on how to evaluate early success or failure and if or when it is best to change therapy. Here, we review the diagnostic techniques currently used in association with clinical findings and propose an approach using a combination of computer tomography, clinical and all available biomarkers and inflammation parameters, especially those positive at baseline, to assess early response in invasive pulmonary aspergillosis. Computed tomography scans should be carried out at regular intervals during early and long-term follow-up. Imaging on day seven, or even earlier in clinically unstable patients, combined with an additional testing of biomarkers and inflammatory markers in between, is needed for a reliable assessment at day 14. If no improvement is seen after 2 weeks of therapy or the clinical condition is deteriorating, a change of antifungal therapy should be considered. Alleged breakthrough infections or treatment failure should undergo early diagnostic workup, including tissue biopsies when possible, to retrieve fungal cultures for resistance testing.

Aspergillus terreus Causing Probable Invasive Aspergillosis in a Patient with Cystic Fibrosis.

Aspergillus terreus may colonize the airways of patients with cystic fibrosis (CF). Whether this merits antifungal treatment is still unclear due to heterogeneous reports regarding its pathogenic potential. Although allergic manifestations are documented, invasive aspergillosis (IA) caused by A. terreus has not been described. We present here one case of probable IA caused by A. terreus, highlighting its role as an emerging agent of IA in CF patients. Voriconazole was effective, and the patient was healthy after 12 weeks of treatment. Serial determination of serum galactomannan level and periodic cultures from respiratory specimens may help in monitoring CF patients by identifying such pathogens. Further studies on the fungal species colonizing the CF airways are warranted, especially in India. This case report suggests A. terreus as a potential agent of IA which should not be ignored, particularly in this patient group.

Invasive Pulmonary Aspergillosis Complicated by Carbapenem-Resistant Pseudomonas aeruginosa Infection During Pembrolizumab Immunotherapy for Metastatic Lung Adenocarcinoma: Case Report and Review of the Literature.

The widespread use of T lymphocyte-associated antigen-4 (CTLA-4) and programmed death (PD)-1 and PD ligand-1 (PDL1)-targeted agents in cancer patients as immunotherapy has raised some issues on their safety profile. Regarding infectious complications, it has emerged that these compounds do not intrinsically increase susceptibility to opportunistic infections, which mainly correlate with the co-administration of systemic immunosuppressive therapy (high-dose corticosteroids and anti-tumor necrosis factors inhibitors) to cure immune-related adverse events (colitis, hepatitis, pneumonitis and pancreatitis), well-known complications of these targeted drugs. These observations lead experts' opinion to suggest primary anti-Pneumocystis prophylaxis in patients undergoing CTLA-4 and PD-1/PDL1 agents who will receive prednisone 20 mg daily for ≥ 4 weeks. Few data on invasive fungal infections in this context are available. We report here a case of probable invasive pulmonary aspergillosis (p-IPA) complicating first-line immunotherapy with pembrolizumab for metastatic lung cancer that was further aggravated by multidrug-resistant Pseudomonas aeruginosa superinfection of fungal cavities; the patient received concurrent systemic corticosteroid therapy as anti-edema treatment for cerebral metastases. Reviewing literature about Aspergillus diseases in subjects receiving CTLA-4 and PD-1 and PDL1-targeted agents, we found three cases of invasive aspergillosis and one case of exacerbation of chronic progressive pulmonary aspergillosis after nivolumab treatment; to the best of our knowledge, this is the first report of p-IPA complicating pembrolizumab immunotherapy. Briefly, in this new setting of biological/targeted drugs, waiting for growing clinical experience, we recommend a high level of alertness in diagnosing any infectious complications.

Pharmacodynamics of the Novel Antifungal Agent F901318 for Acute Sinopulmonary Aspergillosis Caused by Aspergillus flavus.

Background: Aspergillus flavus is one of the most common agents of invasive aspergillosis and is associated with high mortality. The orotomides are a new class of antifungal agents with a novel mechanism of action. An understanding of the pharmacodynamics (PD) of the lead compound F901318 is required to plan safe and effective regimens for clinical use. Methods: The pharmacokinetics (PK) and PD of F901318 were evaluated by developing new in vitro and in vivo models of invasive fungal sinusitis. Galactomannan was used as a pharmacodynamic endpoint in all models. Mathematical PK-PD models were used to describe dose-exposure-response relationships. Results: F901318 minimum inhibitory concentrations (MICs) ranged from 0.015 to 0.06 mg/L. F901318 induced a concentration-dependent decline in galactomannan. In the in vitro model, a minimum concentration:MIC of 10 resulted in suppression of galactomannan; however, values of approximately 10 and 9-19 when assessed by survival of mice or the decline in galactomannan, respectively, were equivalent or exceeded the effect induced by posaconazole. There was histological clearance of lung tissue that was consistent with the effects of F901318 on galactomannan. Conclusions: F901318 is a potential new agent for the treatment of invasive infections caused by A flavus with PDs that are comparable with other first-line triazole agents.

Failure of voriconazole therapy due to acquired azole resistance in Aspergillus fumigatus in a kidney transplant recipient with chronic necrotizing aspergillosis.

Invasive aspergillosis (IA) affects the lungs and disseminates mostly in patients with neutropenia and/or patients who are receiving immunosuppressive and steroid therapies. Despite progress in the diagnosis of and therapy for IA, it is still characterized by a high mortality rate. Currently, voriconazole is considered as the standard therapy for IA. Over recent years, triazole-resistant Aspergillus fumigatus isolates have emerged in the environment due to the use of fungicidal agricultural products, with the risk of developing IA related to a resistant isolate. However, resistance may also develop in patients who are undergoing long-term triazole therapy, particularly in the setting of chronic forms of pulmonary aspergillosis. Herein we describe a kidney transplant recipient who failed to respond to voriconazole therapy due to acquired resistance secondary to the appearance of a de novo mutation (Y121F) in the cyp51A gene during chronic necrotizing pulmonary aspergillosis. The infecting isolate acquired voriconazole resistance in 8 months despite plasma concentrations within the recommended range of the drug, necessitating lobectomy in association with a new antifungal strategy consisting of liposomal amphotericin and caspofungin with a good outcome over 36 months.

Bronchoalveolar Lavage Fluid Cytology in Culture-Documented Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases: Analysis of 67 Episodes.

There is a paucity of studies on the yield of Gomori-methenamine-silver (GMS) staining in bronchoalveolar lavage (BAL) fluid cytology and its comparison with fluorescent dye staining for the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with hematologic malignancies. To that end, we analyzed the yield of direct fungal visualization in BAL fluid cytology with GMS staining, in a series of culture-positive IPA cases in 67 patients with hematologic malignancies, and we compared the results with those of direct examination with calcofluor white staining and BAL fluid galactomannan assays, when available. GMS staining in BAL fluid cytology was positive in 42% of the 67 cases and revealed coinfections in 7 cases. In contrast, only 2/67 (3.6%) BAL fluid samples were positive in direct smears stained with the fluorescent dye calcofluor white. Positive GMS staining results were significantly more frequent in IPA cases with cavitary lesions and IPA cases caused by >1 Aspergillus species, but the proportions of positive cytology results among Aspergillus species were not different.

Aspergillus fumigatus protein phosphatase PpzA is involved in iron assimilation, secondary metabolite production, and virulence.

Metal restriction imposed by mammalian hosts during an infection is a common mechanism of defence to reduce or avoid the pathogen infection. Metals are essential for organism survival due to its involvement in several biological processes. Aspergillus fumigatus causes invasive aspergillosis, a disease that typically manifests in immunocompromised patients. A. fumigatus PpzA, the catalytic subunit of protein phosphatase Z (PPZ), has been recently identified as associated with iron assimilation. A. fumigatus has 2 high-affinity mechanisms of iron acquisition during infection: reductive iron assimilation and siderophore-mediated iron uptake. It has been shown that siderophore production is important for A. fumigatus virulence, differently to the reductive iron uptake system. Transcriptomic and proteomic comparisons between ∆ppzA and wild-type strains under iron starvation showed that PpzA has a broad influence on genes involved in secondary metabolism. Liquid chromatography-mass spectrometry under standard and iron starvation conditions confirmed that the ΔppzA mutant had reduced production of pyripyropene A, fumagillin, fumiquinazoline A, triacetyl-fusarinine C, and helvolic acid. The ΔppzA was shown to be avirulent in a neutropenic murine model of invasive pulmonary aspergillosis. PpzA plays an important role at the interface between iron starvation, regulation of SM production, and pathogenicity in A. fumigatus.

Invasive pulmonary aspergillosis secondary to microwave ablation: a multicenter retrospective study.

PURPOSE: Invasive pulmonary aspergillosis (IPA) is a life-threatening complication of microwave ablation (MWA) during the treatment of primary or metastatic lung tumors. The purpose of this study was to investigate the clinical, radiological and demographic characteristics and treatment responses of patients with IPA after MWA. MATERIALS AND METHODS: From January 2011 to January 2016, all patients who were treated by MWA of their lung tumors from six health institutions were enrolled in this study. Patients with IPA secondary to MWA were identified and retrospectively evaluated for predisposing factors, clinical treatment, and outcome. RESULTS: The incidence of IPA secondary to lung MWA was 1.44% (23/1596). Of the 23 patients who developed IPA, six died as a consequence, resulting in a high mortality rate of 26.1%. Using computed tomography (CT), pulmonary cavitation was the most common finding and occurred in 87.0% (20/23) of the patients. Sudden massive hemoptysis was responsible for one-third of the deaths (2/6). Most patients (22/23) received voriconazole as an initial treatment, and six patients with huge cavities underwent intracavitary lavage. Finally, 17 patients (73.9%) achieved treatment success. CONCLUSIONS: Lung MWA may be an additional host risk factor for IPA, particularly in elderly patients with underlying diseases and in patients who have recently undergone chemotherapy. Early and accurate diagnosis of IPA after MWA is critical for patient prognosis. Voriconazole should be given as the first-line treatment as early as possible. Bronchial artery embolization or intracavitary lavage may be required in some patients.

Murine model to follow hyphal development in invasive pulmonary aspergillosis.

Aspergillus fumigatus is an opportunistic pathogen, the leading cause of invasive and disseminated aspergillosis in systemic immunocompromised patients, and an important cause of mortality. The aim of the present study was to adapt a pulmonary aspergillosis murine model, to determine pathodynamical parameters quantitatively, and to follow the progression of fungal infection in vivo. The nasal inoculation of Aspergillus conidia in mice previously subjected to immunosuppression with cyclophosphamide (CP) turned out to be a more suitable model than that of immunosuppressed with hydrocortisone (HC). The following parameters were found to correlate quantitatively with the progress of the infection: (i) survival rate, (ii) weight loss of mice, (iii) infected focal plaque size, (iv) hyphal density, (v) hyphal length distribution of A. fumigatus, and the (vi) the histopathological status and scores. These parameters will be essential elements for the development of antifungal drugs and therapies, and important for the investigation of the pathogenicity in different strains of A. fumigatus.

Proven Invasive Pulmonary Aspergillosis in Stem Cell Transplant Recipient Due to Aspergillus sublatus, a Cryptic Species of A. nidulans.

Invasive fungal disease represents one of the severe complications in haematopoietic stem cell transplant recipients. We describe a case of a patient treated for relapse of chronic lymphoblastic leukaemia 6 years after HSCT. The patient was treated for invasive pulmonary aspergillosis but died 3 months later from multiple organ failures consisting of haemorrhagic necrotizing fungal pneumonia, refractory chronic hepatic graft versus host disease and cytomegalovirus hepatitis. Autopsy samples revealed histopathological evidence of fungal hyphae and an unusual Aspergillus nidulans-like species was isolated in pure culture. More precise identification was achieved by using scanning electron microscopy of ascospores and sequencing of calmodulin gene, and the isolate was subsequently re-identified as A. sublatus (section Nidulantes) and showed good in vitro susceptibility against all classes of antifungals. Commonly used ITS rDNA region and ß-tubulin gene fail to discriminate A. sublatus from related pathogenic species, especially A. quadrilineatus and A. nidulans. Although this is the first case of proven IPA attributed to A. sublatus, we demonstrated that at least some previously reported infections due to A. quadrilineatus were probably caused by this cryptic species.

Case Series Study of Invasive Pulmonary Aspergillosis.

Diagnosis of invasive pulmonary aspergillosis (IPA) is challenging. The objective of the study was to assess the value of microbiological tests to the diagnosis of IPA in the absence of non-specific radiological data. A retrospective study of 23 patients with suspicion of IPA and positivity of some microbiological diagnostic tests was performed. These tests included conventional microbiological culture, detection of Aspergillus galactomannan (GM) antigen and in some patients (1 â†’ 3)-ß-D-glucan (BDG) and Aspergillus fumigatus DNA using the LightCycler® SeptiFast test. In 10 patients with hematological malignancy, 6 cases were considered 'probable' and 4 'non-classifiable.' In 8 patients with chronic lung disease, 7 cases were classified as 'probable' and 1 as 'proven,' and in 5 patients with prolonged ICU stay (>7 days), there were 2 'proven' cases, 2 'non-classifiable' and 1 putative case. Microbiological culture was positive in 17 cases and 18 Aspergillus spp. were isolated (one mixed culture). A. fumigatus was the most frequent (44.4%) followed by A. tubingensis. The Aspergillus galactomannan (GM) antigen assay was positive in 21 cases (91.3%). The GM antigen and the (1 â†’ 3)-ß-D-glucan (BDG) assays were both performed in 12 cases (52.2%), being positive in 9. The SeptiFast test was performed in 7 patients, being positive in 4. In patients with non-classifiable pulmonary aspergillosis and one or more positive microbiological tests, radiological criteria may not be considered a limiting factor for the diagnosis of IPA.

[The expression of triggering receptor expressed on myeloid cells receptor-1 in Aspergillus infected mice].

Objective: To investigate the expression of triggering receptor expressed on myeloid cells receptor-1 (TREM-1) in plasma and bronchoalveolar lavage fluid (BALF) and its correlation with Galactomannan, IFNγ, IL-6 and IL-10 in Aspergillus infected mice. Methods: Cyclophosphamide(CTX) was intraperitoneally injected and fumigatus spore suspension was inhaled by nose to establish the immunocompromised invasive pulmonary aspergillosis(IPA) mouse model.Healthy controls, immunocompromised only and IPA only groups were also established. Each group had 6 mice. After inoculation, mice were sacrificed. Lung tissue specimens, BALF, and plasma samples were collected. Plasma and BALF soluble TREM-1 (sTREM-1), Galactomannan, IFNγ, IL-6, and IL-10 were detected by ELISA. Results: Positive Aspergillus fumigatus was found by tissue culture in the lung. Infiltration of inflammatory cells, blood congestion and interstitial lung tissue injury were observed in histological sections of both IPA and immunocompromised IPA mice. Compared to IPA group [(453.78±74.18) ng/L, P<0.001; (10.21±1.46) ng/L, P<0.001] and control group [(245.16±65.85) ng/L, P<0.001; (6.60±3.74) ng/L, P<0.001], the plasma and BALF sTREM-1 significantly increased in immunocompromised IPA group [(1 537.64±359.52) ng/L; (20.12±2.72) ng/L]. Compared to control group, both the BALF sTREM-1 in IPA group (P=0.041) and the plasma and BALF Galactomannan, IFNγ, IL-6, and IL-10 levels in IPA and immunocompromised IPA groups were significantly higher (P<0.01). Pearson correlation analysis showed that plasma and BALF sTREM-1 were significantly correlated with Galactomannan (r=0.83, P<0.001; r=0.82, P<0.001), IFNγ (r=0.79, P<0.001; r=0.61, P<0.01), IL-6 (r=0.81, P<0.001; r=0.66, P<0.01), and IL-10 (r=0.70, P=0.001; r=0.54, P=0.02). Conclusions: Plasma and BALF sTREM-1 appears highly expressed in Aspergillus infected mice. sTREM-1 in mice plasma and BALF is closely correlated with Galactomannan, IFNγ, IL-6, and IL-10 levels, which suggests that sTREM-1 has great diagnostic value during invasive fungal infection.

Risk Factors Associated With Early Invasive Pulmonary Aspergillosis in Kidney Transplant Recipients: Results From a Multinational Matched Case-Control Study.

Risk factors for invasive pulmonary aspergillosis (IPA) after kidney transplantation have been poorly explored. We performed a multinational case-control study that included 51 kidney transplant (KT) recipients diagnosed with early (first 180 posttransplant days) IPA at 19 institutions between 2000 and 2013. Control recipients were matched (1:1 ratio) by center and date of transplantation. Overall mortality among cases was 60.8%, and 25.0% of living recipients experienced graft loss. Pretransplant diagnosis of chronic pulmonary obstructive disease (COPD; odds ratio [OR]: 9.96; 95% confidence interval [CI]: 1.09-90.58; p = 0.041) and delayed graft function (OR: 3.40; 95% CI: 1.08-10.73; p = 0.037) were identified as independent risk factors for IPA among those variables already available in the immediate peritransplant period. The development of bloodstream infection (OR: 18.76; 95% CI: 1.04-339.37; p = 0.047) and acute graft rejection (OR: 40.73, 95% CI: 3.63-456.98; p = 0.003) within the 3 mo prior to the diagnosis of IPA acted as risk factors during the subsequent period. In conclusion, pretransplant COPD, impaired graft function and the occurrence of serious posttransplant infections may be useful to identify KT recipients at the highest risk of early IPA. Future studies should explore the potential benefit of antimold prophylaxis in this group.

Clinical Presentation and Determinants of Mortality of Invasive Pulmonary Aspergillosis in Kidney Transplant Recipients: A Multinational Cohort Study.

The prognostic factors and optimal therapy for invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT) remain poorly studied. We included in this multinational retrospective study 112 recipients diagnosed with probable (75.0% of cases) or proven (25.0%) IPA between 2000 and 2013. The median interval from transplantation to diagnosis was 230 days. Cough, fever, and expectoration were the most common symptoms at presentation. Bilateral pulmonary involvement was observed in 63.6% of cases. Positivity rates for the galactomannan assay in serum and bronchoalveolar lavage samples were 61.3% and 57.1%, respectively. Aspergillus fumigatus was the most commonly identified species. Six- and 12-week survival rates were 68.8% and 60.7%, respectively, and 22.1% of survivors experienced graft loss. Occurrence of IPA within the first 6 months (hazard ratio [HR]: 2.29; p-value = 0.027) and bilateral involvement at diagnosis (HR: 3.00; p-value = 0.017) were independent predictors for 6-week all-cause mortality, whereas the initial use of a voriconazole-based regimen showed a protective effect (HR: 0.34; p-value = 0.007). The administration of antifungal combination therapy had no apparent impact on outcome. In conclusion, IPA entails a dismal prognosis among KT recipients. Maintaining a low clinical suspicion threshold is key to achieve a prompt diagnosis and to initiate voriconazole therapy.

Aspergillosis of the Heart and Lung and Review of Published Reports on Fungal Endocarditis.

Invasive aspergillosis (IA) is increasingly diagnosed in high-risk patients. The lesions are usually located in the lungs and/or sinuses, and the fungus may spread haematogenously to different organs; however, involvement of the heart during IA is very rare. We describe a unique case of invasive aspergillosis of the heart septum and the lungs in the allogeneic haematopoietic stem cell transplant recipient.