Fungal Lung Disease Research Articles

Fungal Lung Disease.

Fungal lung disease encompasses a wide spectrum of organisms and associated clinical conditions presenting a significant global health challenge with type and severity determined by underlying host immunity and infecting fungal strain. The most common group of diseases are associated with the filamentous fungus Aspergillus spp. and include allergic bronchopulmonary aspergillosis (ABPA), sensitization, aspergilloma, and chronic and invasive pulmonary aspergillosis. Fungal lung disease remains epidemiologically heterogenous and is influenced by geography, environment, and host comorbidities. Diagnostic modalities continue to evolve and now include novel molecular assays and biomarkers, however, persisting challenges include achieving rapid and accurate diagnosis, particularly in resource-limited settings and in differentiating fungal infection from other pulmonary conditions. Treatment strategies for fungal lung diseases rely mainly on antifungal agents, however, the emergence of drug-resistant strains poses a substantial global threat and adds complexity to existing therapeutic challenges. Emerging antifungal agents and increasing insight into lung mycobiome via may offer fresh and personalized approaches to diagnosis and treatment, while innovative methodologies are required to mitigate drug resistance and adverse effects of treatment. This state-of-the-art review describes the current landscape of fungal lung disease, highlighting key clinical insights, current challenges, and emerging approaches for its diagnosis and treatment.

Artículo traducido] Caracterización y resultados del uso de voriconazol nebulizado en un entorno real: un estudio observacional unicéntrico

ObjectivePulmonary administration of voriconazole involves advantages, including optimization of lung penetration and reduction of adverse effects and interactions. However, there is scarce evidence about its use and there are no commercial presentations for nebulization. We aim to characterize a compounded voriconazole solution for nebulization and describe its use in our center. MethodThis is a retrospective observational study including patients who received nebulized voriconazole to treat fungal lung diseases (infection or colonization). Voriconazole solution was prepared from commercial vials for intravenous administration. ResultsThe pH and osmolarity of voriconazole solutions were adequate for nebulization. Ten patients were included, nine adults and a child. The dosage was 40 mg in adults and 10 mg in the pediatric patient, diluted to a final concentration of 10 mg/ml, administered every 12-24 hours. The median duration of treatment was 139 (range: 26-911) days. There were no reported adverse effects and the drug was not detected in plasma when nebulized only. ConclusionVoriconazole nebulization is well tolerated and it is not absorbed into the systemic circulation; further research is needed to assess its efficacy.

Characterization and real-live results of nebulized voriconazole: A single-center observational study

ObjectivePulmonary administration of voriconazole involves advantages, including optimization of lung penetration and reduction of adverse effects and interactions. However, there is scarce evidence about its use and there are no commercial presentations for nebulization. We aim to characterize a compounded voriconazole solution for nebulization and describe its use in our center. MethodThis is a retrospective observational study including patients who received nebulized voriconazole to treat fungal lung diseases (infection or colonization). Voriconazole solution was prepared from commercial vials for intravenous administration. ResultsThe pH and osmolarity of voriconazole solutions were adequate for nebulization. Ten patients were included, 9 adults and a child. The dosage was 40 mg in adults and 10 mg in the pediatric patient, diluted to a final concentration of 10 mg/ml, administered every 12–24 h. The median duration of treatment was 139 (range: 26–911) days. There were no reported adverse effects and the drug was not detected in plasma when nebulized only. ConclusionVoriconazole nebulization is well-tolerated and it is not absorbed into the systemic circulation; further research is needed to assess its efficacy.

P300 Importance of direct microscopy in respiratory mold infection: a diagnostic dilemma

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PM IntroductionOpportunistic fungal infections are on the rise due to a changing healthcare paradigm worldwide. India is the second most populated country in the world and is experiencing an upward trend in fungal lung diseases.ObjectiveRapid diagnosis of respiratory mold infections by direct microscopy.Material and MethodsWe retrospectively analyzed the mycology of the received respiratory samples; sputum, BAL, or ETT secretion between January 1, 2021 to March 31, 2022. All the samples were processed as per standard mycological procedures. For each sample, two KOH wet mounts were prepared and examined. Samples were inoculated over SDA and blood agar and incubated at 28°0C and 37°C in BOD. Once there was growth, it was processed as per standard protocol.ResultsWe received a total of 109 respiratory samples from suspected respiratory fungal infections of which early morning sputum samples 84 (77%) were the predominant followed by BAL samples 25 (23%). Most of the enrolled patients were male 73(67%) with a mean age of 48 years. Among 109 samples, 83 (76%) were shown to be fungal elements by KOH wet mount while 26 (24%) were KOH negative. A total of 53 (48.6%) samples were culture-positive Aspergillus flavus30(27%), was found to be the most common species isolated followed by A. fumigatus 16 (14.6%), miscellaneous11(10%), Aspergillus. species 5 (4.5%), and A. terreus 2 (1.8%).ConclusionConsidering the findings of KOH mount in our study, we would like to emphasize that this is a very simple, rapid, and cost-effective laboratory method with high diagnostic sensitivity when correlated with clinical findings, radiological findings, and host factors.Further, it has been found to be very dependable for making decisions to start empirical antifungal therapy early by clinicians.

Progress and challenges in fungal lung disease in cystic fibrosis.

This review is an overview of the recent progress made for the diagnosis and understanding of fungal lung disease in people with cystic fibrosis (CF), with a focus on Aspergillus fumigatus , the most common filamentous fungus in the CF airway. Currently, the longstanding question of the clinical significance of Aspergillus fumigatus and other fungi in CF respiratory cultures, in the absence of allergy, remains. Clinical criteria and biomarkers are needed to classify fungal lung disease and determine who may warrant therapy. Several retrospective and prospective studies have described the prevalence of A. fumigatus and other fungi in the CF lung and factors contributing to the changes in fungal epidemiology. Selective fungus culture testing for the detection of fungi in CF sputa has been well studied, yet a standardized fungus culture protocol has yet to be defined. Culture-independent molecular studies and other fungal diagnostic testing have been conducted in the CF population, leading to efforts to better understand the clinical role of these tests. Recent works have aimed to determine whether chronic A. fumigatus colonization is associated with lung disease progression measured by FEV 1 percentage predicted, structural lung disease, lung clearance index and respiratory quality-of-life. However, the existing knowledge gaps remain: definition of a fungal respiratory infection, the association between fungal infection and clinical outcomes, and indications for antifungal therapy. Significant progress has been made for the detection and diagnosis of fungal lung disease. Yet, the role and impact of A. fumigatus and other fungal infections on respiratory health in people with CF remains to be determined.

18F-FSPG PET imaging for the evaluation of indeterminate pulmonary nodules.

Background18F-fluorodeoxyglucose (FDG) PET/CT is recommended for evaluation of intermediate-risk indeterminate pulmonary nodules (IPNs). While highly sensitive, the specificity of FDG remains suboptimal for differentiating malignant from benign nodules, particularly in areas where fungal lung diseases are prevalent. Thus, a cancer-specific imaging probe is greatly needed. In this study, we tested the hypothesis that a PET radiotracer (S)-4-(3-[18F]-fluoropropyl)-L-glutamic acid (FSPG) improves the diagnostic accuracy of IPNs compared to 18F-FDG PET/CT.MethodsThis study was conducted at a major academic medical center and an affiliated VA medical center. Twenty-six patients with newly discovered IPNs 7-30mm diameter or newly diagnosed lung cancer completed serial PET/CT scans utilizing 18F-FDG and 18F-FSPG, without intervening treatment of the lesion. The scans were independently reviewed by two dual-trained diagnostic radiology and nuclear medicine physicians. Characteristics evaluated included quantitative SUVmax values of the pulmonary nodules and metastases.ResultsA total of 17 out of 26 patients had cancer and 9 had benign lesions. 18F-FSPG was negative in 6 of 9 benign lesions compared to 7 of 9 with 18F-FDG. 18F-FSPG and 18F-FDG were positive in 14 of 17 and 12 of 17 malignant lesions, respectively. 18F-FSPG detected brain and intracardiac metastases missed by 18F-FDG PET in one case, while 18F-FDG detected a metastasis to the kidney missed by 18F-FSPG.ConclusionIn this pilot study, there was no significant difference in overall diagnostic accuracy between 18F-FSPG and 18F-FDG for the evaluation of IPNs and staging of lung cancer. Additional studies will be needed to determine the clinical utility of this tracer in the management of IPNs and lung cancer.

Using Artificial Intelligence in Fungal Lung Disease: CPA CT Imaging as an Example

This positioning paper aims to discuss current challenges and opportunities for artificial intelligence (AI) in fungal lung disease, with a focus on chronic pulmonary aspergillosis and some supporting proof-of-concept results using lung imaging. Given the high uncertainty in fungal infection diagnosis and analyzing treatment response, AI could potentially have an impactful role; however, developing imaging-based machine learning raises several specific challenges. We discuss recommendations to engage the medical community in essential first steps towards fungal infection AI with gathering dedicated imaging registries, linking with non-imaging data and harmonizing image-finding annotations.

Frequent Pet Contact as Risk Factor for Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis.

Aspergillus fumigatus (Af) frequently colonizes the respiratory tract of patients with cystic fibrosis (CF). Af is associated with loss of pulmonary function and allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity fungal lung disease. Environmental factors have impact on CF patients’ lung function variation. The aim of this nationwide questionnaire survey was to investigate the amount of CF patients with frequent pet contact including pet species and to examine the potential impact of frequent pet contact on the occurrence of Af colonization and ABPA diagnosis in these patients. The survey was carried out in 31 German CF centers in 2018. A total of 1232 who completed the surveys were included, and statistical analysis was performed by chi-squared test. Within the study cohort 49.8% of subjects (n = 614; CF patients < 18years: 49.4%, n = 234; ≥ 18years: 50.1%, n = 380) reported frequent contact to pets, of which 60.7% reported frequent contact to dogs, 42.3% to cats and other animals. Of those with frequent pet contact, 71.8% (n = 441) had contact to one pet or more pets from the same family. Af colonization was not significantly associated with frequent pet contact. ABPA diagnosis was documented in 16.7% (n = 206) of all included CF patients and was significantly associated with frequent pet contact (18.9%, n = 116, p = 0.042), confirming previous single center examinations. Particularly, patients with frequent contact to dogs showed an increased ABPA prevalence of 21.3%. Frequent pet contact might be a risk factor for ABPA. CF patients who are sensitized to Af should be informed about the increased risk to develop an ABPA by frequent pet contact. Patients with recurrent onset of ABPA should be evaluated in terms of frequent pet contact.

The diagnosis and management of respiratory tract fungal infection in cystic fibrosis: A UK survey of current practice.

Aspergillus fumigatus is commonly found in the airways of patients with cystic fibrosis (CF), and allergic bronchopulmonary aspergillosis (ABPA) is the most recognized associated clinical condition. However, accurate diagnosis remains challenging, and there is a paucity of clinical trials to guide clinical management of fungal disease. The aim of this survey was to assess the variability in current practice across the UK in diagnosis and management of fungal lung disease in CF patients. A 21 question anonymous online survey was sent to 94 paediatric and adult CF consultants in the UK. The response rate was 60.6% (32 adult physicians, 25 pediatricians) with 55 full and 2 partially completed surveys. For a first diagnosis of ABPA 20 (35.1%) treat with prednisolone alone, 38 (66.7%) use prednisolone with itraconazole and 2 (3.5%) choose voriconazole. Only 5 (8.8%) treat with prednisolone alone for a 1st relapse, 33 (58%) used prednisolone with itraconazole. To reduce treatment, 21 (36.8%) decrease steroids to zero over time and maintain azole therapy, 18 (31.6%) stop the azole and steroid after a fixed time, and 5 (8.8%) stop the azole after a fixed time and maintain a small steroid dose. Thirty-eight (66.7%) respondents believe Aspergillus colonization of the airway can cause clinical deterioration, and 37 (66.1%) would treat this. Scedosporium apiospermum infection has been diagnosed and treated by 35 (61.4%) of respondents. Results of this survey highlight the variance in clinical practice and the limited evidence available to guide management of fungal infection in CF.

An Estimate of the Burden of Fungal Disease in Norway.

The aim of this study was to examine the burden of fungal disease in Norway, contributing to a worldwide effort to improve awareness of the needs for better diagnosis and treatment of such infections. We used national registers and actual data from the Departments of Microbiology from 2015 and estimated the incidence and/or prevalence of superficial, allergic and invasive fungal disease using published reports on specific populations at risk. One in 6 Norwegians suffered from fungal disease: Superficial skin infections (14.3%: 745,600) and recurrent vulvovaginal candidiasis in fertile women (6%: 43,123) were estimated to be the most frequent infections. Allergic fungal lung disease was estimated in 17,755 patients (341/100,000). Pneumocystis jirovecii was diagnosed in 262 patients (5/100,000), invasive candidiasis in 400 patients (7.7/100,000), invasive aspergillosis in 278 patients (5.3/100,000) and mucormycosis in 7 patients (0.1/100,000). Particular fungal infections from certain geographic areas were not observed. Overall, 1.79% of the population was estimated to be affected by serious fungal infections in Norway in 2015. Even though estimates for invasive infections are small, the gravity of such infections combined with expected demographic changes in the future emphasizes the need for better epidemiological data.

Profile and functional analysis of small RNAs derived from Aspergillus fumigatus infected with double-stranded RNA mycoviruses

BackgroundMycoviruses are viruses that naturally infect and replicate in fungi. Aspergillus fumigatus, an opportunistic pathogen causing fungal lung diseases in humans and animals, was recently shown to harbour several different types of mycoviruses. A well-characterised defence against virus infection is RNA silencing. The A. fumigatus genome encodes essential components of the RNA silencing machinery, including Dicer, Argonaute and RNA-dependent RNA polymerase (RdRP) homologues. Active silencing of double-stranded (ds)RNA and the generation of small RNAs (sRNAs) has been shown for several mycoviruses and it is anticipated that a similar mechanism will be activated in A. fumigatus isolates infected with mycoviruses.ResultsTo investigate the existence and nature of A. fumigatus sRNAs, sRNA-seq libraries of virus-free and virus-infected isolates were created using Scriptminer adapters and compared. Three dsRNA viruses were investigated: Aspergillus fumigatus partitivirus-1 (AfuPV-1, PV), Aspergillus fumigatus chrysovirus (AfuCV, CV) and Aspergillus fumigatus tetramycovirus-1 (AfuTmV-1, NK) which were selected because they induce phenotypic changes such as coloration and sectoring. The dsRNAs of all three viruses, which included two conventionally encapsidated ones PV and CV and one unencapsidated example NK, were silenced and yielded characteristic vsiRNAs together with co-incidental silencing of host fungal genes which shared sequence homology with the viral genomes.ConclusionsVirus-derived sRNAs were detected and characterised in the presence of virus infection. Differentially expressed A. fumigatus microRNA-like (miRNA-like) sRNAs and small interfering RNAs (siRNAs) were detected and validated. Host sRNA loci which were differentially expressed as a result of virus infection were also identified. To our knowledge, this is the first study reporting the sRNA profiles of A. fumigatus isolates.

Temperature during conidiation affects stress tolerance, pigmentation, and trypacidin accumulation in the conidia of the airborne pathogen Aspergillus fumigatus.

Asexual spores (conidia) are reproductive structures that play a crucial role in fungal distribution and survival. As fungal conidia are, in most cases, etiological agents of plant diseases and fungal lung disease, their stress resistance and interaction with their hosts have drawn increasing attention. In the present study, we investigated whether environmental temperature during conidiation affects the stress tolerance of the conidia of the human pathogenic fungus Aspergillus fumigatus. Conidia from a 25°C culture showed a lower tolerance to heat (60°C) and oxidative (H2O2) stresses and a marked resistance to ultraviolet radiation exposure, compared with those produced at 37 and 45°C. The accumulation of trehalose was lower in the conidia from the 25°C culture. Furthermore, the conidia from the 25°C culture showed darker pigmentation and increased transcripts of dihydroxynaphthalene (DHN)-melanin biosynthesis-related genes (i.e., pksP, arp1, and arp2). An RNA-sequencing analysis revealed that the transcription level of the trypacidin (tpc) gene cluster, which contains 13 genes, was sharply and coordinately activated in the conidia from the 25°C culture. Accordingly, trypacidin was abundant in the conidia from the 25°C culture, whereas there was little trypacidin in the conidia from the 37°C culture. Taken together, these data show that the environmental temperature during conidiation affects conidial properties such as stress tolerance, pigmentation, and mycotoxin accumulation. To enhance our knowledge, we further explored the temperature-dependent production of DHN-melanin and trypacidin in clinical A. fumigatus isolates. Some of the isolates showed temperature-independent production of DHN-melanin and/or trypacidin, indicating that the conidia-associated secondary metabolisms differed among the isolates.

Allergic Bronchopulmonary Aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA), a progressive fungal allergic lung disease, is a common complication of asthma or cystic fibrosis. Although ABPA has been recognized since the 1950s, recent research has underscored the importance of Th2 immune deviation and granulocyte activation in its pathogenesis. There is also strong evidence of widespread under-diagnosis due to the complexity and lack of standardization of diagnostic criteria. Treatment has long focused on downregulation of the inflammatory response with prolonged courses of oral glucocorticosteroids, but more recently concerns with steroid toxicity and availability of new treatment modalities has led to trials of oral azoles, inhaled amphotericin, pulse intravenous steroids, and subcutaneously-injected anti-IgE monoclonal antibody omalizumab, all of which show evidence of efficacy and reduced toxicity.

224. A Gene Therapy Clinical Study of a Patient with X-Linked Chronic Granulomatous Disease

BACKGROUND: X-linked Chronic granulomatous disease (X-CGD) is a primary immunodeficiency disease characterized by failure of the nicotinamide adenine dinucleotide phosphate enzyme system in phagocytes to produce reactive oxygen species (ROS). This disorder derives from defects in the CYBB gene encoding gp91phox and leads to recurrent infection and hyper-inflammation, occasionally represented by CGD-associated colitis (CGD colitis). Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for X-CGD, and in Europe and America, gene therapy clinical trials have been performed to patients who have no HLA-matched donor. To assess the safety and efficacy of hematopoietic stem cell gene therapy, we commenced a retroviral gene therapy clinical study using a busulfan-based preconditioning treatment regimen for CGD patients. METHODS AND PATIENT: The patient was a 27-year- old man with X-CGD. His condition was complicated by refractory subcutaneous abscess, fungal lung disease, lymphadenitis and CGD colitis, and he did not have an appropriate HLA-matched donor for HSCT. Granulocyte colony-stimulating factor -mobilized CD34+ stem cells were transduced with an MFGS-based retrovirus vector encoding the therapeutic gene of CYBB ex vivo, and infused back to the patient after busulfan-based preconditioning. Clinical and biochemical assessments were performed to evaluate the safety and efficacy of retrovirus gene therapy. RESULTS: After engraftment of 6.5×106/kg of CD34+ cells including 76% of gp91phox expressing cells, the gene-modified phagocytes appeared in peripheral blood after day +14. Dihydrorhodamine (DHR) flow cytometry assay demonstrated that the 2.3% of neutrophils in peripheral blood produced ROS, and a vector insert copy number was 2.63 per DHR+ neutrophil at day +95. His clinical symptoms of subcutaneous abscess and CGD colitis improved at almost the same time. The retrovirus insertion site of gene-modified peripheral blood cells revealed that there was no evidence of abnormal growth of clones with MDS-EVI1, SETBP1 or PRDM16 integrants at day +63. At day +182, gene marking of peripheral blood decreased to about 0.1% of neutrophils. PCR quantification of vector gene marking showed a vector insert copy number of 0.17 and 0.04 per neutrophil at day +95 and day +182, respectively. A vector insertion copy of bone marrow cells was 0.08 per marrow cell at day +183, suggesting that a reduction of gene-modified CD34+ stem cells would cause a decrease of gp91phox expressing phagocytes in peripheral blood. CONCLUSION: The therapeutic gene itself does not confer a growth advantage on the transduced cells in CGD, which would impact on the long-term gene marking and the withdrawal of clonal expansion. As other studies have reported that residual ROS production could contribute to the survival of CGD patients, the presence of gene-modified ROS-producing phagocytes led to the improvement of severe infection in our patient.

ImmunoPET/MR imaging allows specific detection of Aspergillus fumigatus lung infection in vivo

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease caused by the fungus Aspergillus fumigatus, and is a leading cause of invasive fungal infection-related mortality and morbidity in patients with hematological malignancies and bone marrow transplants. We developed and tested a novel probe for noninvasive detection of A. fumigatus lung infection based on antibody-guided positron emission tomography and magnetic resonance (immunoPET/MR) imaging. Administration of a [(64)Cu]DOTA-labeled A. fumigatus-specific monoclonal antibody (mAb), JF5, to neutrophil-depleted A. fumigatus-infected mice allowed specific localization of lung infection when combined with PET. Optical imaging with a fluorochrome-labeled version of the mAb showed colocalization with invasive hyphae. The mAb-based newly developed PET tracer [(64)Cu]DOTA-JF5 distinguished IPA from bacterial lung infections and, in contrast to [(18)F]FDG-PET, discriminated IPA from a general increase in metabolic activity associated with lung inflammation. To our knowledge, this is the first time that antibody-guided in vivo imaging has been used for noninvasive diagnosis of a fungal lung disease (IPA) of humans, an approach with enormous potential for diagnosis of infectious diseases and with potential for clinical translation.

Locally Invasive Fungal Lung Disease and Exercise-Induced Pulmonary Hemorrhage: A Deadly Interplay of Cavitary Aspergilloma Kinetics and Capillary Hemodynamics

SESSION TITLE: Chest Infections II: Student Resident Case Report Posters SESSION TYPE: Student/Resident Case Report Poster PRESENTED ON: Tuesday, October 27, 2015 at 01:30 PM - 02:30 PM INTRODUCTION: Aspergilloma is an opportunistic fungal disease which typically forms in cavitary lung. We report the case of an enlarging aspergilloma in an immunocompromised patient with pulmonary hemorrhage precipitated by strenuous cardiopulmonary exercise. CASE PRESENTATION: A 58-year old female presented to our emergency department in February 2015 with hemoptysis. She underwent a multi-stage treadmill cardiac stress test seven days earlier to evaluate exertional dyspnea, achieving a heart rate of 143 and a peak blood pressure of 175/100. She subsequently coughed several teaspoons of blood streaked sputum for the next week. Prior to admission she ran vigorously at her gym triggering large-volume hemoptysis (130-150ml), prompting hospital admission. Her past medical history included fully treated pulmonary tuberculosis with residual localized cystic bronchiectasis in right upper lobe with a suspected aspergilloma and Crohn's disease in remission on azathioprine and mesalamine. On arrival her blood pressure was 162/86, pulse 72, afebrile with a resting SpO2 of 100% on air. Examination was significant for coarse breath sounds in the right upper chest. Labs revealed a hemoglobin of 14.5g/dl, WBC 6,600/nL, platelets 223,000/nL, INR 0.9 and PTT 20secs. Initial CT imaging demonstrated an enlarged lobulated right apical cavity containing a soft tissue mass, which had increased in size from 19.6mm to 22.4mm over 4 months. The patient was treated with piperacillin-tazobactam for an infectious exacerbation of bronchiectasis and her blood pressure was tightly controlled with beta-blockade. Her hemoptysis ceased by hospital day 4 without need for blood transfusion or endovascular intervention. Azathioprine was discontinued and voriconazole was initiated to minimize the risk of local fungal invasion. She was counselled on the importance of blood pressure control and advised to change her exercise routine from running to a low impact activity such as cycling to minimize aspergilloma movement and prevent shearing forces within the cavity. DISCUSSION: Aspergillomas confer significant morbidity to predisposed individuals with potential for life-threatening hemoptysis. Immunosuppression may facilitate local invasion of hyphae into the adjacent lung parenchyma. The delicate granulation tissue lining the cavity is probably susceptible to pendulous forces of the aspergilloma during high impact exercise such as running and jumping resulting in capillary rupture and bleeding1. CONCLUSIONS: There is little guidance on what lifestyle modification is appropriate for patients with aspergillomas. Providers should consider the exercise tolerance of each patient, their immune status and size of the aspergilloma before recommending a type and intensity of exercise that can safely be undertaken. Reference #1: Corrin, B. (2011). Pathology of the Lungs. Churchill Livingstone/Elsevier DISCLOSURE: The following authors have nothing to disclose: Haider Ali, Erika Diaz-Narvaez, Armando Cuesta, Schantal Polanco, Chang Shim, Virginia Chung No Product/Research Disclosure Information

Survival following lung resection in immunocompromised patients with pulmonary invasive fungal infection.

Pulmonary invasive fungal infections (IFIs) are associated with high mortality in patients being treated for haematological malignancy. There is limited understanding of the role for surgical lung resection and outcomes in this patient population. This is a retrospective cohort of 50 immunocompromised patients who underwent lung resection for IFI. Patient charts were reviewed for details on primary malignancy and treatment course, presentation and work-up of IFI, reasons for surgery, type of resection and outcomes including postoperative complications, mortality, disease relapse and survival. Analysis was also performed on two subgroups based on year of surgery from 1990-2000 and 2001-2014. The median age was 39 years (range: 5-64 years). Forty-seven patients (94%) had haematological malignancies and 38 (76%) underwent haematopoietic stem cell transplantation (HSCT). Surgical indications included haemoptysis, antifungal therapy failure and need for eradication before HSCT. The most common pathogen was Aspergillus in 34 patients (74%). Wedge resections were performed in 32 patients (64%), lobectomy in 9 (18%), segmentectomy in 2 (4%) and some combination of the 3 in 7 (14%) for locally extensive, multifocal disease. There were 9 (18%) minor and 14 (28%) major postoperative complications. Postoperative mortality at 30 days was 12% (n = 6). Acute respiratory distress syndrome was the most common cause of postoperative death. Overall 5-year survival was 19%. Patients who had surgery in the early period had a median survival of 24 months compared with 5 months for those who had surgery before 2001 (P = 0.046). At the time of death, 15 patients (30%) had probable or proven recurrent IFI. Causes of death were predominantly related to refractory malignancy, fungal lung disease or complications of graft versus host disease (GVHD). Patients who had positive preoperative bronchoscopy cultures had a trend towards worse survival compared with those with negative cultures (hazard ratio: 1.80, P = 0.087). Surgical resection of IFI in immunocompromised patients is associated with high perioperative mortality. Long-term survival is limited by recurrent malignancy, persistent fungal infection and GVHD but has improved in recent years. Selection for surgical resection is difficult in this patient population, but should be carefully considered in those who are symptomatic, or have failed antifungal treatment.

Aerosolized amphotericin B lipid complex as adjunctive treatment for fungal lung infection in patients with cancer-related immunosuppression and recipients of hematopoietic stem cell transplantation.

Aerosolized amphotericin B lipid complex (aeABLC) has been successfully used to prevent fungal disease. Experience with aeABLC as treatment of fungal lung disease is limited. We evaluated the safety and efficacy of aeABLC adjunct therapy for fungal lung disease in a retrospective study of 32 immunosuppressed adults. All values are given as±standard deviation. National Cancer Institute-designated Comprehensive Cancer Center. Acute leukemia (69%) and severe neutropenia (63%) were common. Fifty-six percent of patients had undergone allogeneic hematopoietic stem cell transplantation 185±424 days prior to aeABLC was commenced. High-dose corticosteroids were administered during aeABLC in 28% of patients. Fungal lung disease was proven or probable in 41% of patients. Most patients (78%) received concurrent systemic antifungal therapy for a median of 14±18days before aeABLC. The median cumulative aeABLC dose was 1050±2368 mg, and the median duration of aeABLC therapy was 28±130days. Most patients (78%) received 50mg aeABLC twice daily. Partial or complete resolution of fungal lung disease was noted in 50% of patients. In three patients (9%) modest cough, mild bronchospasm, and transient chest pain with accompanying nausea and vomiting resolved completely after discontinuation of aeABLC. No patient required hospitalization for drug toxicity or had a serious (grade III or IV) drug-related adverse event. Treatment with aeABLC was tolerated without serious toxicity and may be considered in the setting of severe immunosuppression, cancer, and/or hematopoietic stem cell transplantation in patients with difficult-to-treat fungal lung disease.

Pulmonary Disease in Primary Immunodeficiency Disorders

Pulmonary complications are an extremely common manifestation of primary immunodeficiency disorders (PIDD). Infections are the most common abnormality and can lead to specific pulmonary complications. Patients with PIDD can present with a variety of manifestations such as recurrent bacterial, viral, or fungal pneumonia, bronchiectasis, granulomatous disease, and obstructive or restrictive lung disease. Some of the PIDDs can have unique lung abnormalities seen with specific defects. This review covers the respiratory manifestations seen in patients with a variety of primary immunodeficiencies. This recognition is important to reduce morbidity and mortality in these patients and possibly prevent the occurrence of chronic lung damage.

Voriconazole and Posaconazole Improve Asthma Severity in Allergic Bronchopulmonary Aspergillosis and Severe Asthma with Fungal Sensitization

Rationale and objectives. Severe asthma with fungal sensitization (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) are progressive allergic fungal lung diseases whose effective treatment remains to be established. Current treatment with itraconazole is associated with a 40% failure rate and adverse events (AEs). We assessed the effect of voriconazole or posaconazole as second- and third-line therapies. Methods. We conducted a retrospective review of adult asthmatic patients with either ABPA or SAFS receiving voriconazole or posaconazole. Clinical, radiological, and immunological evaluation was used to assess response. Results. There were 25 patients, ABPA (n = 20) or SAFS (n = 5), 10 males, median age = 58 years. All patients had failed itraconazole (n = 14) or developed AEs (n = 11). There were 33 courses of therapy analyzed, 24 with voriconazole and 9 with posaconazole. Clinical response to voriconazole was observed in 17/24 (70%) patients at 3 months, 15/20 (75%) at 6 months, and 12/16 (75%) at 12 months compared with 7/9 (78%) at 3, 6, and 12 months for posaconazole. Eighteen of 24 (75%) patients discontinued oral corticosteroids (OCS), 12 of them within 3 months of therapy. Asthma severity was downgraded from severe to moderate (n = 8) and moderate to mild (n = 1) asthma in 9 of 24 (38%) asthmatic patients. There was a marked reduction in OCS and short-acting beta-2 agonist use, health-care utilization due to asthma, and improvement in overall health status. Furthermore, there was a statistically significant reduction in immunological markers appearing at 9 months (p = .008) for total IgE and at 12 months for radioallergosorbent test IgE for Aspergillus fumigatus (p = .0056). Six of 23 (26%) patients on voriconazole had AEs requiring discontinuation before 6 months compared with none on posaconazole (p = .15). Four relapsed (57%), one at 3 months and three at 12 months after discontinuation. Conclusion. Both voriconazole and posaconazole are potentially effective alternative treatment options for SAFS and ABPA and may improve asthma control and reduce severity, though larger prospective studies are required to support these retrospective study findings.