Efficacy and safety of caspofungin for the treatment of invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

OBJECTIVES: We assessed the efficacy of a 3-week primary or salvage caspofungin regimen in patients with chronic obstructive pulmonary disease (COPD) and concomitant proven or suspected invasive pulmonary aspergillosis (IPA). METHODS: Forty-four patients were treated with an initial loading caspofungin dose of 70 mg, followed by a daily dose of 50 mg for 20 days. The main efficacy endpoint was clinical effectiveness. Secondary endpoints included the clinical efficacy of caspofungin after 1 week, therapeutic efficacy based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, the sensitivity of different Aspergillus strains to caspofungin in vitro, and the safety of caspofungin. RESULTS: An assessment of 42 patients in the intention-to-treat group revealed efficacy rates of 33.33% within 1 week and 38.10% within 3 weeks. According to the EORTC/MSG criteria, the treatment success rate was 38.10%. The success rate of first-line treatment was 54.76%, whereas salvage treatment had a success rate of 45.24%. No adverse events were reported among the participants. CONCLUSIONS: Caspofungin is effective and safe as an initial or salvage treatment for patients with IPA and COPD.

Successful treatment of angioinvasive aspergillosis causing diaphragmatic rupture with bowel perforation and cerebral aspergillosis in a patient with FLT3-mutated acute myeloid leukemia: A case report.

RATIONALE: Throughout the clinical course of acute myeloid leukemia (AML), aspergillosis infection remains a significant determinant of treatment outcomes and survival. To emphasize the importance of early diagnosis and appropriate application of integrated therapeutic approaches, we present a case of AML patient who survived through angioinvasive aspergillosis infection causing diaphragmatic rupture with bowel perforation and cerebral aspergillosis during active AML treatment. PATIENT CONCERNS: A 39-year old male with FLT3-mutated AML was transferred to our hospital due to persistent fever after induction therapy. DIAGNOSIS AND INTERVENTIONS: During voriconazole treatment for his invasive pulmonary aspergillosis, the patient was diagnosed with colon perforation at splenic flexure and suspected perforation of left diaphragm with communication with left pleural space. Although pancytopenic, emergency laparotomy was performed with granulocyte transfusion. Also, dual antifungal therapy with voriconazole and micafungin was applied. With supportive care, he was able to successfully complete 3 cycles of consolidation using tyrosine kinase inhibitor. However, 80 days after the last chemotherapy, the patient experienced seizure caused by a single 1.5 cm sized enhancing mass in the right occipital lobe. Diagnostic and therapeutic mass removal was carried out, and pathology-confirmed cerebral aspergillosis was diagnosed. OUTCOMES: The patient's neurologic symptoms are resolved and he is leukemia free, but remains on voriconazole for his cerebral aspergillosis till this day. CONCLUSIONS: Our case highlights the importance of timely integrated intervention and adequate underlying disease control in treatment of invasive aspergillosis in immunocompromised patients. Such rigorous efforts can save even the most seemingly dismal case.

In vitro study on aspects of molecular mechanisms underlying invasive aspergillosis caused by gliotoxin and fumagillin, alone and in combination.

Gliotoxin (GT) and fumagillin (FUM) are mycotoxins most abundantly produced by Aspergillus fumigatus during the early stages of infection to cause invasive aspergillosis (IA). Therefore, we hypothesized that GT and FUM could be the possible source of virulence factors, which we put to test adopting in vitro monoculture and the novel integrated multiple organ co-culture (IdMOC) of A549 and L132 cell. We found that (i) GT is more cytotoxic to lung epithelial cells than FUM, and (ii) GT and FUM act synergistically to inflict pathology to the lung epithelial cell. Reactive oxygen species (ROS) is the master regulator of the cytotoxicity of GT, FUM and GT + FUM. ROS may be produced as a sequel to mitochondrial damage and, thus, mitochondria are both the source of ROS and the target to ROS. GT-, FUM- and GT + FUM-induced DNA damage is mediated either by ROS-dependent mechanism or directly by the fungal toxins. In addition, GT, FUM and GT + FUM may induce protein accumulation. Further, it is speculated that GT and FUM inflict epithelial damage by neutrophil-mediated inflammation. With respect to multiple organ cytotoxicity, GT was found to be cytotoxic at IC50 concentration in the following order: renal epithelial cells < type II epithelial cells < hepatocytes < normal lung epithelial cells. Taken together, GT and FUM alone and in combination contribute to exacerbate the damage of lung epithelial cells and, thus, are involved in the progression of IA.

Invasive pulmonary aspergillosis in patients with influenza infection: A retrospective study and review of the literature.

INTRODUCTION: There has been a rapid increase in the number of influenza and invasive pulmonary aspergillosis (IPA) co-infection. OBJECTIVES: To explore the risk factors and predictors of a poor prognosis in influenza and IPA co-infection. METHODS: We included patients with confirmed influenza during the 2017-2018 influenza season and cases of influenza and IPA co-infection in the literature. RESULTS: A total of 64 patients with influenza infection were admitted to ICU. Of these patients, 18 were co-infected with IPA. Others were assigned to the control group (n = 46). A total of 45 patients from the literature were added to the IPA group (n = 63). A multivariate logistic regression suggested that influenza patients who were given steroids after ICU admission, who had a white blood count (WBC) of more than 10*109 /L on ICU admission and whose CT findings manifested as multiple nodules and cavities might have a higher risk of developing IPA. Compared to survivors, non-survivors had higher sequential organ failure assessment (SOFA) scores (16 ± 4 points vs 8 ± 4 points, P < 0.001), lower CD4+ T cell counts on ICU admission [315 (83-466) cells/µL vs 152 (50-220) cells/µL, P = 0.031] and more requirement extracorporeal membrane oxygenation (ECMO) support [13 (50%) vs 7 (18.9%), P = 0.015]. CONCLUSIONS: Influenza patients who are given steroids after ICU admission, who have WBCs of greater than 10*109 /L on ICU admission, and whose CT imaging shows multiple nodules and cavities might have a high risk of IPA. Higher SOFA scores, CD4+ T cell counts lower than 200 cells/µL on ICU admission and more ECMO requirement might be predictors of a poor prognosis.

Utility of serum galactomannan antigen testing combined with chest computed tomography for early diagnosis of invasive pulmonary aspergillosis in patients with hematological malignancies with febrile neutropenia after antifungal drug treatment.

OBJECTIVE: To investigate the value of serum galactomannan antigen (GM) testing combined with chest computed tomography (CT) as a noninvasive method for early diagnosis of invasive pulmonary aspergillosis (IPA) in patients with hematological malignancies with febrile neutropenia after antifungal drug treatment. METHODS: We retrospectively analyzed the data of 376 patients with febrile neutropenia from January 2015 to August 2017. All patients were given broad-spectrum antibiotics and divided into the control group (effective antibiotic treatment, no antifungal drugs given) and the observational group (ineffective antibiotic treatment, antifungal drugs given). The serum GM testing, chest CT, and microbiological examination findings were compared between the two groups. RESULTS: The false-positive rates of GM testing for IPA in the control and observational groups were 4.04% and 8.65%, respectively, and the false-negative rates in the two groups were 1.10% and 9.62%, respectively. Sixty-five patients in the observational group and 11 in the control group had typical features of CT imaging. CONCLUSION: Clinical weekly screening of serum GM and chest CT may be an effective combined approach to the early diagnosis of IPA in patients with febrile neutropenia, even if they have undergone antifungal treatment.

Invasive Tracheobronchial Aspergillosis in a Lung Transplant Recipient Receiving Belatacept as Salvage Maintenance Immunosuppression: A Case Report.

INTRODUCTION: The association between belatacept, a CD28 costimulation blocker, and invasive mycoses is unclear. CASE REPORT: We describe a patient who initiated belatacept 3 years after lung transplantation and developed invasive tracheobronchial aspergillosis, a disease encountered almost exclusively within the first 6 months after transplantation. CONCLUSIONS: Belatacept may have played a causative role. Until more data are available, belatacept should be used cautiously after lung transplantation.

Chronic necrotizing pulmonary aspergillosis in a patient treated with a tumor necrosis factor-alpha inhibitor.

Tumor necrosis factor (TNF)-alpha is a pro-inflammatory cytokine that plays an important role in the pathogenesis of a variety of autoimmune diseases. TNF-alpha inhibitors have been shown to offer clinical benefits in the treatment of autoimmune and inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis (AS), and Crohn's disease. Occasionally, these agents have been associated with infectious complications because of their immunosuppressive activity. Globally, several cases of infections associated with TNF-alpha inhibitors have been reported. However, Aspergillus infection associated with etanercept is very rare. We report a case of chronic necrotizing pulmonary aspergillosis in a 51-year-old man with AS that developed after treatment with etanercept.