Invasive Pulmonary Disease Research Articles

Performance of rapid on-site evaluation of touch imprints of bronchoscopic biopsies or lung tissue biopsies for the diagnosis of invasive pulmonary filamentous fungi infections in non-neutropenic patients.

The diagnosis of invasive pulmonary fungal disease depends on histopathology and mycological culture; there are few studies on touch imprints of bronchoscopic biopsies or lung tissue biopsies for the diagnosis of pulmonary filamentous fungi infections. The purpose of the present study was to explore the detection accuracy of rapid on-site evaluation of touch imprints of bronchoscopic biopsies or lung tissue biopsies for the filamentous fungi, and it aims to provide a basis for initiating antifungal therapy before obtaining microbiological evidence. We retrospectively analyzed the diagnosis and treatment of 44 non-neutropenic patients with invasive pulmonary filamentous fungi confirmed by glactomannan assay, histopathology, and culture from February 2017 to December 2023. The diagnostic positive rate and sensitivity of rapid on-site evaluation for these filamentous fungi identification, including diagnostic turnaround time, were calculated. Compared with the final diagnosis, the sensitivity of rapid on-site evaluation was 81.8%, and the sensitivity of histopathology, culture of bronchoalveolar lavage fluid, and glactomannan assay of bronchoalveolar lavage fluid was 86.4%, 52.3%, and 68.2%, respectively. The average turnaround time of detecting filamentous fungi by rapid on-site evaluation was 0.17 ± 0.03 hours, which was significantly faster than histopathology, glactomannan assay, and mycological culture. A total of 29 (76.3%) patients received earlier antifungal therapy based on ROSE diagnosis and demonstrated clinical improvement. Rapid on-site evaluation showed good sensitivity and accuracy that can be comparable to histopathology in identification of pulmonary filamentous fungi. Importantly, it contributed to the triage of biopsies for further microbial culture or molecular detection based on the preliminary diagnosis, and the decision on early antifungal therapy before microbiological evidence is available.

Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus.

Molds are environmental fungi that can cause disease in immunocompromised individuals. The most common pathogenic mold is Aspergillus fumigatus, which is typically inhaled into the lungs and causes invasive pulmonary disease. In a subset of these patients, this infection can spread from the lungs to other organs including the brain, resulting in cerebral aspergillosis. How A. fumigatus causes brain disease is not well understood and these infections are associated with extremely high mortality rates. Thus, we developed an animal model to study the pathogenesis of cerebral aspergillosis to better understand this disease and develop better treatments for these life-threatening infections.

Clinical Uses of Inhaled Antifungals for Invasive Pulmonary Fungal Disease: Promises and Challenges.

The role of inhaled antifungals for prophylaxis and treatment of invasive fungal pneumonias remains undefined. Herein we summarize recent clinically relevant literature in high-risk groups such as neutropenic hematology patients, including those undergoing stem cell transplant, lung and other solid transplant recipients, and those with sequential mold lung infections secondary to viral pneumonias. Although there are several limitations of the available data, inhaled liposomal amphotericin B administered 12.5 mg twice weekly could be an alternative method of prophylaxis in neutropenic populations at high risk for invasive fungal pneumonia where systemic triazoles are not tolerated. In addition, inhaled amphotericin B has been commonly used as prophylaxis, pre-emptive, or targeted therapy for lung transplant recipients but is considered as a secondary alternative for other solid organ transplant recipients. Inhaled amphotericin B seems promising as prophylaxis in fungal pneumonias secondary to viral pneumonias, influenza, and SARS CoV-2. Data remain limited for inhaled amphotericin for adjunct treatment, but the utility is feasible.

The relationship between organising pneumonia and invasive mould disease in patients with haematologic malignancy.

Organising pneumonia (OP) is reported in patients with haematologic malignancy suspected of having invasive mould disease, yet little is known about this relationship. To investigate molecular evidence of invasive mould pneumonia in paraffin-embedded lung tissues from histologically diagnosed OP patients with suspected invasive mould pneumonia. Patients with haematologic malignancy suspected to have invasive pulmonary mould disease who underwent lung biopsy at a tertiary hospital, Seoul, South Korea, between 2008 and 2020, were retrospectively reviewed. To find molecular evidence of fungal infection, PCR assay was used to detect Aspergillus- and Mucorales-specific DNA within OP lung tissue sections. Forty-seven patients with suspected invasive mould pneumonia underwent lung biopsy and 15 (32%) were histologically diagnosed as OP without any evidence of fungal hyphae. Of these 15 patients, 3 (20%) received allogenic haematopoietic stem cell transplantation prior to developing OP. Before biopsy, 2 and 13 patients had probably and possible invasive mould disease, respectively. The median antifungal treatment length was 81 [8-114]days, and the median steroid treatment dosage was 0.35 mg/kg/day for 36 days (methylprednisolone equivalent doses), respectively. After biopsy, three patients with possible invasive mould infection revealed probable invasive pulmonary aspergillosis. From the 15 paraffin-embedded lung tissues, 6 (40%) exhibited positive PCR assay results for detecting Aspergillus- and Mucorales-specific DNA. More than one third of OP cases in patients with suspected invasive mould pneumonia exhibited molecular evidence of invasive mould infection by fungus-specific PCR in lung tissues, likely associated with concurrent or prior fungal infection.

Clinical characteristics and outcomes of invasive and non-invasive fusariosis in South Korea.

Invasive fusariosis mainly affects immunocompromised patients including haematopoietic stem cell transplant recipients and those with haematologic malignancy. There are limited studies on invasive fusariosis in the Asia-Pacific region. To describe the clinical characteristics and outcomes of invasive and non-invasive fusariosis in South Korea. From 2005 to 2020, patients with fusariosis who met the revised European Organisation for Research and Treatment of Cancer and the Mycoses Study Group criteria for the definition of proven or probable invasive fusariosis, and those with non-invasive fusariosis were retrospectively reviewed in a tertiary medical centre in Seoul, South Korea. Overall, 26 and 75 patients had invasive and non-invasive fusariosis, respectively. Patients with invasive fusariosis commonly had haematologic malignancy (62%), were solid organ transplant recipients (23%), and had a history of immunosuppressant usage (81%). In non-invasive fusariosis, diabetes mellitus (27%) and solid cancer (20%) were common underlying conditions. Disseminated fusariosis (54%) and invasive pulmonary disease (23%) were the most common clinical manifestations of invasive fusariosis; skin infection (48%) and keratitis (27%) were the most common manifestations of non-invasive fusariosis. Twenty-eight-day and in-hospital mortalities were high in invasive fusariosis (40% and 52%, respectively). In multivariate analysis, invasive fusariosis (adjusted odds ratio, 9.6; 95% confidence interval 1.3-70.8; p=.03) was an independent risk factor for 28-day mortality. Patients with invasive fusariosis were frequently immunocompromised, and more than half had disseminated fusariosis. Invasive fusariosis was associated with poor prognosis.

Pulmonary Aspergillosis Silently Presenting as Pneumothorax in Children with Leukemia: A Report of Three Cases.

AbstractAspergillosis causes invasive pulmonary disease in patients with hematological malignancies. Children with invasive pulmonary aspergillosis (IPA) usually have nonspecific radiographic findings unlike cavitary lesions commonly seen in adults. Pneumothorax due to rupture of peripheral fungal lesion may be a severe complication in patients with neutropenia. Here, we describe three children during induction chemotherapy for B-lymphoblastic leukemia with pneumothorax as a presenting feature of pulmonary aspergillosis.

Computed tomography-based radiomics for identifying pulmonary cryptococcosis mimicking lung cancer.

Pulmonary cryptococcosis (PC) is an invasive pulmonary fungal disease, and nodule/mass-type PC may mimic lung cancer (LC) in imaging appearance. Thus, an accurate diagnosis of nodule/mass-type PC is beneficial for appropriate management. However, the differentiation of nodule/mass-type PC from LC through computed tomography (CT) is still challenging. To develop and externally test a CT-based radiomics model for differentiating nodule/mass-type PC from LC. In this retrospective study, patients with nodule/mass-type PC or LC who underwent non-enhanced chest CT were included: Institution 1 was for the training set, and institutions 2 and 3 were for the external test set. Large quantities of radiomics features were extracted. The radiomics score (Rad-score) was calculated using the linear discriminant analysis, and a subsequent fivefold cross-validation was performed. A combined model was developed by incorporating Rad-score and clinical factors. Finally, the models were tested with an external test set and compared using the area under the receiver operating characteristic curve (AUC). A total of 168 patients (45 with PC and 123 with LC) were in the training set, and 72 (36 with PC and 36 with LC) were in the external test set. Of the 81 patients with PC, 30 were immunocompromised (37%). Rad-score, comprising 18 features, had an AUC of 0.844 after fivefold cross-validation, which was lower than that (AUC = 0.943, p = 0.003) of the combined model integrating Rad-score, age, lobulation, pleural retraction, and patches. In the external test set, Rad-score and the combined model obtained good predictive performance (AUC = 0.824 for Rad-score, and 0.869 for the combined model). Moreover, the combined model outperformed the clinical model in the cross-validation and external test (0.943 vs. 0.810, p <0.001; 0.869 vs. 0.769, p = 0.011). The proposed combined model exhibits a good differential diagnostic performance between nodule/mass-type PC and LC. The CT-based radiomics analysis has the potential to serve as an effective tool for the differentiation of nodule/mass-type PC from LC in clinical practice.

BTK Inhibitors Impair Platelet-Mediated Antifungal Activity.

In recent years, the introduction of new drugs targeting Bruton’s tyrosine kinase (BTK) has allowed dramatic improvement in the prognosis of patients with chronic lymphocytic leukemia (CLL) and other B-cell neoplasms. Although these small molecules were initially considered less immunosuppressive than chemoimmunotherapy, an increasing number of reports have described the occurrence of unexpected opportunistic fungal infections, in particular invasive aspergillosis (IA). BTK represents a crucial molecule in several signaling pathways depending on different immune receptors. Based on a variety of specific off-target effects on innate immunity, namely on neutrophils, monocytes, pulmonary macrophages, and nurse-like cells, ibrutinib has been proposed as a new host factor for the definition of probable invasive pulmonary mold disease. The role of platelets in the control of fungal growth, through granule-dependent mechanisms, was described in vitro almost two decades ago and is, so far, neglected by experts in the field of clinical management of IA. In the present study, we confirm the antifungal role of platelets, and we show, for the first time, that the exposure to BTK inhibitors impairs several immune functions of platelets in response to Aspergillus fumigatus, i.e., the ability to adhere to conidia, activation (as indicated by reduced expression of P-selectin), and direct killing activity. In conclusion, our experimental data suggest that antiplatelet effects of BTK inhibitors may contribute to an increased risk for IA in CLL patients.

Characteristics of Invasive Pulmonary Fungal Diseases Diagnosed by Pathological Examination.

Objective To explore the characteristics of invasive pulmonary fungal disease and the spectrum of pathogens causing invasive pulmonary fungal disease diagnosed by pathological examination using fungal stains. Methods Patients with an invasive pulmonary fungal disease diagnosed by histopathological analysis through the use of fungal stains (including Grocott's methenamine silver and periodic acid-Schiff stains) were included in this study. The clinical records, radiological reports, pathology, and fungal culture results were reviewed. Results Forty-eight invasive pulmonary fungal disease patients diagnosed by histopathological analysis in the Tianjin Haihe Hospital (including 8 cases obtained by pulmonary resection, 35 cases by fiberoptic bronchoscopic biopsy, and 5 cases by percutaneous lung biopsy) were included. There were 24 male and 24 female patients, aged 21–80 years (53 ± 13 years). There were 37 cases of pulmonary aspergillosis, 4 cases of pulmonary cryptococcosis, 2 cases of pulmonary mucormycosis, and 5 in which pathogens were not determined due to limited tissue availability. Among 48 cases, 32 specimens were submitted to fungal culture. No fungus was detected in culture, although 26 cases of fungus infections were diagnosed by histopathological analysis. Only 3 cases were consistent between histopathological and culture results. In 3 cases, the pathogen was identified as Aspergillus spp. by the histopathological analysis, while the contrasting fungal culture results identified Candida albicans. Conclusion Candida albicans pneumonia was rare, while aspergillosis was common in invasive pulmonary fungal disease diagnosed by histopathological analysis. The majority of patients with an invasive pulmonary fungal disease were culture-negative. Although culture can clarify the fungal pathogen species, it has low sensitivity. Pathological examination with fungal stains has its advantages in diagnosing fungal disease; therefore, more attention should be paid to the role of pathological examination in the diagnosis of fungal disease.

Clinical analysis of 16 cases of pulmonary cryptococcosis in patients with normal immune function.

Pulmonary cryptococcosis (PC) is an invasive pulmonary fungal disease caused by Cryptococcus neoformans or Cryptococcus gattii. Cryptococcus is the opportunistic pathogen. Immune damage and chronic consumptive diseases are the high risk. The prevalence of cryptococcus infection is 5% to 10% in individuals with weakened immune function. In recent years, with the application of glucocorticoids, antitumor drugs, and broad-spectrum antibiotics, the prevalence of cryptococcal infection has increased yearly. Cryptococcus infection can also occur in normal people without underlying diseases. One in every 100,000 individuals with normal immune function is also affected, but these cases are often misdiagnosed due to inadequate understanding and low awareness of PC in individuals with normal immune function. In this study, we investigated the clinical characteristics of PC in patients with normal immune function to improve the diagnosis and treatment of these cases. We retrospectively analyzed the clinical, imaging and pathological data of 16 patients with pulmonary cryptococcosis treated at Beijing Shijitan Hospital between 2010 and 2017. Of the 16 patients with disseminated cryptococcosis, 6 were men, and 10 were women; their ages were 35 to 76 years (median: 53 years). Initial symptoms were cough, sputum, chest pain, and fever. Thirteen patients had a history of chronic disease or tumor, including diabetes and bronchial asthma (n=2), simple hypertension (n=2), chronic bronchitis (n=2), diabetes and hypertension (n=5), previous tuberculosis (n=1), and previous lung cancer surgery (n=1). Chest computed tomography (CT) in these 16 patients showed single or multiple nodules and masses (n=14), lobar consolidation (n=1), and diffuse mixed lesions (n =1). Lung biopsy showed granulomatous lesions in these 16 patients. Cryptococcus neoformans was identified with Grocott's methenamine silver and Grocott's methenamine silver (GMS) stains. Fourteen patients received fluconazole alone; two patients with intracranial infection received fluconazole combined with amphotericin B. Five patients improved significantly, and nine patients improved with significant lesion absorption. The clinical manifestations of PC are nonspecific in patients with normal immune function. Lung biopsy and cryptococcus antigen tests of cerebrospinal fluid are valuable diagnostic aids. Fluconazole is an effective treatment for disseminated cryptococcal infection.

Central Role of IL-23 and IL-17 Producing Eosinophils as Immunomodulatory Effector Cells in Acute Pulmonary Aspergillosis and Allergic Asthma.

Aspergillus fumigatus causes invasive pulmonary disease in immunocompromised hosts and allergic asthma in atopic individuals. We studied the contribution of lung eosinophils to these fungal diseases. By in vivo intracellular cytokine staining and confocal microscopy, we observed that eosinophils act as local sources of IL-23 and IL-17. Remarkably, mice lacking eosinophils had a >95% reduction in the percentage of lung IL-23p19+ cells as well as markedly reduced IL-23 heterodimer in lung lavage fluid. Eosinophils killed A. fumigatus conidia in vivo. Eosinopenic mice had higher mortality rates, decreased recruitment of inflammatory monocytes, and decreased expansion of lung macrophages after challenge with conidia. All of these functions underscore a potential protective role for eosinophils in acute aspergillosis. Given the postulated role for IL-17 in asthma pathogenesis, we assessed whether eosinophils could act as sources of IL-23 and IL-17 in models where mice were sensitized to either A. fumigatus antigens or ovalbumin (OVA). We found IL-23p19+ IL-17AF+ eosinophils in both allergic models. Moreover, close to 95% of IL-23p19+ cells and >90% of IL-17AF+ cells were identified as eosinophils. These data establish a new paradigm in acute and allergic aspergillosis whereby eosinophils act not only as effector cells but also as immunomodulatory cells driving the IL-23/IL-17 axis and contributing to inflammatory cell recruitment.

ENose technology can detect and classify human pathogenic molds in vitro: a proof-of-concept study of Aspergillus fumigatus and Rhizopus oryzae

Invasive pulmonary mold disease (IPMD) is often fatal in neutropenic patients. This is because IPMD is difficult to diagnose timely, especially when non-Aspergillus molds are the causative agent, as they are usually not associated with a positive galactomannan assay. In 2013 we showed that exhaled breath analysis might be used to diagnose invasive aspergillosis through profiling of patterns in exhaled volatile organic compounds (VOCs) by electronic nose (eNose) technology. The current study aimed to determine (1) whether molds can be discriminated from other microorganisms (using two mold species: Aspergillus fumigatus and a pathogenic mold not associated with a positive galactomannan assay, i.c. Rhizopus oryzae) and (2) whether both molds can be discriminated from each other.First, we cultured strains of Streptococcus pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, A. fumigatus and R. oryzae in separate airtight bottles. We examined whether an eNose (Cyranose 320) could discriminate the headspaces of bottles with molds from those with bacteria/yeasts. Second, we examined whether an eNose could discriminate A. fumigatus and R. oryzae. Diagnostic algorithms were created using canonical discriminant analysis after principle component analysis. Primary outcome parameter was the validated accuracy.The eNose discriminated A. fumigatus from bacteria/yeasts with a cross-validated accuracy of 92.9% (sensitivity 95.2%, specificity 91.9%). The eNose had an accuracy (validated using split-half analysis) of 100% in discriminating A. fumigatus from R. oryzae.Our study suggests that an eNose can identify and classify molds in vitro. This warrants prospective in vivo studies aimed at detecting and classifying IPMD using exhaled breath.

Who to Vax: A free online tool to identify adults for pneumococcal vaccination

We live in an exciting but sometimes overwhelming time to be practicing medicine. The evidence base for population-based decision making is rapidly advancing and continually changing. At the same time, individual patient details and their clinical relevance may fall through the cracks in our complex integrated medical system, requiring vigilance on our part for capturing those details and for improving systems of care.1 Integrating a personal, patient-centered history and examination with evidence-based guidelines is the new art of medicine. Deciding which version of pneumococcal vaccine to give an adult patient epitomizes the complexity of this integration of personalized care and guidelines. It is now recommended that healthy adults without medical comorbidities receive any form of pneumococcal vaccination until the age of 65 years. At the same time, vaccination against disease-causing serotypes of pneumococcus is known to be an important intervention for prevention of invasive pneumococcal disease in a variety of preexisting comorbid conditions and age groups,2,3 and for these groups, there are both age- and disease-specific recommendations on which version of the vaccine to give. The Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts who develop recommendations on use of vaccines in the civilian population of the United States, recommends pneumococcal vaccination as beneficial for patients with immunosuppressed states, cigarette smokers, patients with asthma, patients with chronic obstructive pulmonary disease, and other patients who cross our doors routinely.4 For example, patients with asthma are in a higher risk category for invasive pulmonary disease caused by pneumococcus,5–8 and remembering to vaccinate them may yield higher prevention dividends per vaccine than other groups.9

Predicting essential genes for identifying potential drug targets in Aspergillus fumigatus

BackgroundAspergillus fumigatus (Af) is a ubiquitous and opportunistic pathogen capable of causing acute, invasive pulmonary disease in susceptible hosts. Despite current therapeutic options, mortality associated with invasive Af infections remains unacceptably high, increasing 357% since 1980. Therefore, there is an urgent need for the development of novel therapeutic strategies, including more efficacious drugs acting on new targets. Thus, as noted in a recent review, “the identification of essential genes in fungi represents a crucial step in the development of new antifungal drugs”. Expanding the target space by rapidly identifying new essential genes has thus been described as “the most important task of genomics-based target validation”. ResultsIn previous research, we were the first to show that essential gene annotation can be reliably transferred between distantly related four Prokaryotic species. In this study, we extend our machine learning approach to the much more complex Eukaryotic fungal species. A compendium of essential genes is predicted in Af by transferring known essential gene annotations from another filamentous fungus Neurospora crassa. This approach predicts essential genes by integrating diverse types of intrinsic and context-dependent genomic features encoded in microbial genomes. The predicted essential datasets contained 1674 genes. We validated our results by comparing our predictions with known essential genes in Af, comparing our predictions with those predicted by homology mapping, and conducting conditional expressed alleles. We applied several layers of filters and selected a set of potential drug targets from the predicted essential genes. Finally, we have conducted wet lab knockout experiments to verify our predictions, which further validates the accuracy and wide applicability of the machine learning approach. ConclusionsThe approach presented here significantly extended our ability to predict essential genes beyond orthologs and made it possible to predict an inventory of essential genes in Eukaryotic fungal species, amongst which a preferred subset of suitable drug targets may be selected. By selecting the best new targets, we believe that resultant drugs would exhibit an unparalleled clinical impact against a naive pathogen population. Additional benefits that a compendium of essential genes can provide are important information on cell function and evolutionary biology. Furthermore, mapping essential genes to pathways may also reveal critical check points in the pathogen's metabolism. Finally, this approach is highly reproducible and portable, and can be easily applied to predict essential genes in many more pathogenic microbes, especially those unculturable.

Clinical correlates of herpes simplex virus type 1 loads in the lower respiratory tract of critically ill patients

BackgroundThe significance of isolation of herpes simplex virus (HSV) type 1 from the lower respiratory tract in critically ill patients on mechanical ventilation is still unclear. In the current study, we used polymerase chain reaction techniques to quantify HSV-1 to further evaluate its role. ObjectivesThe hypothesis was that high loads reflect invasive pulmonary disease related to prolonged mechanical ventilation and increased mortality, as opposed to shedding from the upper respiratory tract, which leads to lower viral loads. Study designWe prospectively studied 77 consecutive patients admitted to the intensive care unit and analyzed 136 tracheal aspirates or bronchoalveolar lavage fluids, taken when clinically indicated in the diagnostic workup of fever, radiologic pulmonary infiltrates, progressive respiratory insufficiency or combinations. Samples were cultured for bacteria and yeasts according to routine microbiological methods and HSV-1 loads were determined by real time quantitative PCR. Viral loads were expressed per number of cells recovered. ResultsHSV-1 load was directly related to the simplified acute physiology score II (rs=0.47, P=0.04) when the first specimen taken proved positive for HSV-1. HSV-1 positivity concurred with Candida spp. colonization. Patients with and without a HSV-1 load did not differ with respect to pulmonary and systemic courses and vital outcomes. ConclusionsThe data suggest that HSV-1 in the lower respiratory tract originates from shedding in the upper respiratory tract in about 30% of critically ill patients, following immune suppression and reactivation, without invasively infecting the lung. No attributable mortality was observed.

Aspergillosis in Solid Organ Transplantation

Invasive aspergillosis (IA) occurs in 1–15% of the solid organ transplant (SOT) recipients. Mortality rate in transplant recipients with IA historically has ranged from 65% to 92% (1–4). However, currently reported mortality rate in IA among SOT recipients is 22% (5). An estimated 9.3– 16.9% of all deaths in transplant recipients in the first year have been considered attributable to IA (6). Although the outcomes have improved in the current era, IA remains a significant posttransplant complication in SOT recipients. The review herein discusses the epidemiologic characteristics, risk factors, diagnostic laboratory assays and the approach to antifungal prophylaxis and treatment of IA in SOT recipients.

English

Psuedallescheria boydii is a common soil fungus that is increasingly reported as a human pathogen. Lung is the most common extra cutaneous site of infections .Invasive pulmonary disease is seen usually in an immunocompromised host. We are reporting an unusual first case of invasive pulmonary pseudoallescheria sis in an immunocompetent patient from Central India.Microscopy of bronchoalveolar lavage of a treated and cured patient of past pulmonary tuberculosis revealed hyphae (approx 3-5 µ) which were septate & dichotomously branched resembling aspergillus species.The organism was cultured & identified as P.boydii. . Previously recognized causative agent of disease in an immunocompromised host is now causing disease in immunocompetent host.

Antifungal Prophylaxis in Lung Transplantation

Fungal infections are among the most serious complications of lung transplantation. The 1-year cumulative incidence of invasive fungal infections in lung transplant recipients is 6 to 10%, which is higher than most other solid organ transplant recipients. Aspergillus spp. are the most common etiologic agents, but Candida spp., non-Aspergillus mycelial fungi, Cryptococcus, Pneumocystis, and endemic mycoses can cause active infections in this population. Clinical manifestations of fungal infection in lung transplant recipients are protean, and include invasive pulmonary disease, airway and anastomotic infections, posttransplant empyemas, and disseminated infections. Most centers employ either universal or targeted antifungal prophylaxis in some form, but the agents, doses, durations, and monitoring strategies vary widely from one center to another. This review discusses the salient fungal organisms responsible for infection in lung transplant recipients and management strategies for prevention.

Invasive sinonasal disease due to dematiaceous fungi in immunocompromised individuals: case report and review of the literature

Invasive dematiaceous fungal sinusitis is an uncommon and aggressive disease in immunocompromised individuals. We report a unique case of invasive Exserohilum sinusitis in a pregnant, immunocompromised woman. After treating the woman with pregnancy-induced aplastic anemia and invasive Exserohilum sinusitis and pulmonary disease, we performed a Medline/PubMed review of invasive dematiaceous fungal sinonasal disease in immunocompromised individuals. Twelve cases of proven and one case of probable invasive sinonasal dematiaceous fungal disease in immunocompromised patients are reported in the English-language literature. The majority of patients had underlying hematological conditions. The crude mortality was high, with over half of the patients dying from presumed complications of the underlying immunosuppression. Successful outcomes were associated with surgical debridement, aggressive antifungal use, and a reduction of immunosuppression. The optimal treatment for immunocompromised patients with invasive dematiaceous fungal disease is not known. The role of newer triazoles, posaconazole and voriconazole, appears promising, however more clinical data are needed. Definitive diagnosis requires tissue biopsy and successful treatment is associated with reduction of immunosuppression, aggressive surgical debulking, and systemic antifungal therapy.

Human Lung Mast Cells Mediate Pneumococcal Cell Death in Response to Activation by Pneumolysin

Mast cells are emerging as contributors to innate immunity. Mouse mast cells have a pivotal role in protection against bacterial infection, and human cord blood-derived mast cells reduce bacterial viability in culture. The objectives of this study were to determine whether human lung mast cells (HLMCs) might be protective against pneumococcal lung infection through direct antimicrobial activity. Tissue-derived HLMCs and the human mast cell lines HMC-1 and LAD2 were cocultured with wild-type and mutant pneumococci, and viability and functional assays were performed. Mast cells were also stimulated with purified pneumolysin. HLMCs killed wild-type serotype-2 (D39) pneumococci in coculture but had no effect on an isogenic pneumolysin-deficient (PLN-A) pneumococcus. D39 wild-type, but not PLN-A pneumococci, induced the release of leukotriene C4 from human mast cells in a dose-dependent manner, which was not accompanied by histamine release. Stimulation of mast cells with sublytic concentrations of purified pneumolysin replicated this effect. Furthermore, pneumolysin induced the release of the cathelicidin LL-37 from HLMCs, purified LL-37 reduced pneumococcal viability, and neutralizing Ab to LL-37 attenuated mast cell-dependent pneumococcal killing. In addition, at high concentrations, all pneumococcal strains tested reduced HLMC viability through a combination of pneumolysin and H2O2-dependent mechanisms. HLMCs exhibit direct antimicrobial activity to pneumococci through their activation by pneumolysin. This antimicrobial activity is mediated, in part, by the release of LL-37 from HLMCs. This suggests that mast cells provide an early warning system and potentially limit pneumococcal dissemination early in the course of invasive pulmonary pneumococcal disease.