The role of surgery for invasive pulmonary aspergillosis in paediatric hemato-oncology patients-Can we better define it?

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a serious condition with high morbidity and mortality in paediatric patients with cancer, haematological diseases or immunodeficiencies with or without allogeneic haematopoietic stem cell transplantation (HSCT). The role of surgical intervention for the management of IPA has scarcely been investigated. OBJECTIVES: The aim of this study was to present a single center experience of management of IPA in paediatric patients of an oncological ward, to determine the short and long-term outcomes after thoracic surgical interventions, and to outline the indications of surgical interventions in selected patients. PATIENTS/METHODS: We conducted a retrospective study of 44 paediatric patients with proven and probable IPA treated in our institution between January 2003 and December 2021. The primary endpoint was the overall survival after surgical interventions. Secondary endpoints included post-operative morbidity and mortality. RESULTS: The median age at diagnosis of IPA in our cohort was 11.79 years (range 0.11-19.6). The underlying conditions were malignancies in 34 (77%) patients and haematological or immunological disorders with allogeneic HSCT in 9 (23%) patients. We performed thoracic surgical interventions in 10 (22.7%) patients. Most patients received a video assisted thoracic surgery. Only one patient died within 90 days after surgery with a median follow-up time of 50 months. No other major post-operative complications occurred. The calculated 5-year survival rate from IPA for patients after surgical intervention with curative intention was 57% and 56% for patients without (p = .8216). CONCLUSIONS: IPA resulted in relevant morbidity and mortality in our paediatric patient cohort. Thoracic surgical interventions are feasible and may be associated with prolonged survival as a part of multidisciplinary approach in selected paediatric patients with IPA. Larger scale studies are necessary to investigate the variables associated with the necessity of surgery.

Caso clínico: Síndrome de distrés respiratorio del adulto en paciente COVID-19 en ventilación mecánica con aspergilosis pulmonar invasiva / Clinical case: Adult respiratory distress syndrome in COVID-19 patient on mechanical ventilation with invasive pulmonary aspergillosis

The bibliography on the management of the COVID-19 patient in intensive care units is increasing. Research and publication of results help to optimize the management of these patients and the consequent improvement of results. We present the case of a patient admitted to intensive care due to adult respiratory distress syndrome secondary to COVID-19 pneumonia and personal history of liver transplantation the previous year and pulmonary hypertension under treatment. During admission, the patient requires pronation, neuromuscular blockers, and nitric oxide. Invasive aspergillosis is diagnosed and requires percutaneous tracheostomy.

La bibliografía sobre el manejo del paciente COVID-19 en las unidades de cuidados intensivos va en aumento. La investigación y publicación de resultados ayudan a la optimización del manejo de estos pacientes y la mejora consecuente de resultados. Presentamos el caso de un paciente que ingresa en cuidados intensivos (UCI) por síndrome de distrés respiratorio del adulto secundario a neumonía COVID-19 y antecedentes de trasplante hepático el año previo e hipertensión pulmonar en tratamiento. Durante el ingreso, el paciente precisa pronación, relajación neuromuscular y óxido nítrico. Se diagnostica de aspergilosis invasiva y precisa traqueostomía percutánea.

Posaconazole Tablets in Real-Life Lung Transplantation: Impact on Exposure, Drug-Drug Interactions, and Drug Management in Lung Transplant Patients, Including Those with Cystic Fibrosis.

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations (C0) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were <0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure. The tacrolimus (TRL) and everolimus (ERL) C0 measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively (P = 0.001* [asterisk means that statistical test is significant]), and the PSZ C0 exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively (P < 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL C0/dose ratio (C0/D) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution (P = 0.034*). The ERL C0/D was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI; P = 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients.

Clinical outcome and prognostic factors associated with invasive pulmonary aspergillosis: An 11-year follow-up report from Taiwan.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) has high mortality rate but prognostic factors are not well established. The aim of our study was to evaluate the trend in in-hospital mortality over a period of 11 years and identify factors affecting the clinical outcomes of patients with IPA. METHOD: We conducted a nationwide inpatient population study using data from the Taiwan National Health Insurance Research Database. A total of 407 IPA patients from 2002 to 2012 were included in the study. Differences in demographics, comorbidities, and treatment were evaluated between in-hospital death group and survival group. Multivariate analysis was also performed to identify risk factors for mortality. RESULT: Male patients represented 63.14% of the patients (n = 257) and the mean age was 53.15 ± 20.93 years. Hematological cancer (n = 216, 53.07%) and diabetes mellitus (n = 75, 18.43%) were the most common underlying conditions. The overall case fatality rate was 30.22% with female slightly higher then male (32.67% versus 28.79%). The in-hospital case fatality rate increased since 2002 and peaked in 2006. It then declined over time with an in-hospital mortality of 25% in 2012. The in-hospital death group had a higher intubation rate (p<0.0001), a longer ICU stay (p = 0.0062), higher percentages of DM (p = 0.0412) and COPD (p = 0.0178), and a lower percentage of hematological cancer (p = 0.0079) as compared to survivor. The in-hospital death group was more likely to have steroid treatment (p<0.0001), develop acute renal failure (p<0.0001) and other infectious diseases (p = 0.0008) during hospitalization. Multivariate analysis identified female gender, older age (≥ 65 years old), intubation, bone marrow transplantation, acute renal failure, other infectious diseases and steroid use as predictive factors for mortality. CONCLUSION: The present study shows the trend in mortality among patients with IPA over an 11-year period. Female gender, older age, intubation, bone marrow transplantation, acute renal failure, other infectious diseases and steroid use were identified as risk factors for mortality.

Complete surgical resection and short-term survival in acute invasive fungal rhinosinusitis.

BACKGROUND: Acute invasive fungal rhinosinusitis (AIFR) is a fulminant fungal infection seen in patients who are immunocompromised. Due to its rarity, there is little evidence regarding the appropriate antifungal treatment regimen, especially the degree of surgical intervention. OBJECTIVE: To assess factors that impact short-term survival in AIFR as defined by survival to hospital discharge and to develop a staging system to predict survival and complete surgical resection. METHODS: Fifty-four patients with histopathologically diagnosed AIFR who met inclusion criteria were identified between 1984 and 2014. Patient characteristics, disease extent, treatment modality, and short-term survival data were collected. Univariate analysis was performed to assess for factors associated with survival and increased likelihood of surgical resection. RESULTS: Of 52 patients with adequate documentation, 36 (69.2%) survived their hospital stay. Complete surgical resection was the only factor associated with improved survival (survival, 95.5%; p < 0.01). A surgical staging system was proposed to guide probability of complete resection and overall prognosis, with stage I disease limited to the nasal cavity, stage II involving the paranasal sinuses, stage III involving the orbit, and stage IV with skull base or intracranial extension. The χ2 analyses showed a decreased likelihood of complete surgical resection with stage III or IV disease compared with stage I (resection, 90.9%) (stage III resection, 37.5% [p = 0.01]; stage IV resection, 16.7% [p = 0.002]). There was a decreased likelihood of survival associated with increasing disease stage compared with stage I (survival, 100%) (stage II survival, 60% [p = 0.009]; stage III survival, 62.5% [p = 0.02]; stage IV survival, 54.6%, [p = 0.006]). CONCLUSION: Although further studies are needed to define specific treatment protocols, analysis of these data indicated that endoscopic sinus surgery with the goal of complete surgical resection may provide the best survival outcomes in select patients when complete surgical resection can be performed. Our staging system represents the first attempt to predict surgical success and prognosis in patients with AIFR.

Invasive Aspergillus infection requiring lobectomy in a CYP2C19 rapid metabolizer with subtherapeutic voriconazole concentrations.

Individuals who carry the CYP2C19*17 gain-of-function allele have lower voriconazole exposure and are therefore at risk of failing therapy. Utilizing CYP2C19 genotype to optimize voriconazole dosage may be a cost-effective method of improving treatment outcomes. However, there are limited data describing what initial voriconazole dosage should be used in those with increased CYP2C19 metabolic capacity. Herein, we present a case report of a pediatric CYP2C19 rapid metabolizer (i.e., CYP2C19*1/*17) requiring a voriconazole dosage of 14 mg/kg twice daily (usual pediatric dosage ranges from 7 to 9 mg/kg twice daily). This case report supports the clinical utility of using CYP2C19 genotype to guide voriconazole dosing, and provides data for establishing an initial voriconazole dose in pediatric CYP2C19 rapid metabolizers.

[Effects of surgical resection of pulmonary lesions to the relapse of pulmonary aspergillosis in allogeneic hematopoietic stem cell transplant recipients with invasive pulmonary aspergillosis].

OBJECTIVE: To explore the rate of breakthrough invasive pulmonary aspergillosis (IPA) in patients receiving surgical resection of pulmonary aspergillosis lesions prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A retrospective analysis was conducted between January 2007 and June 2014. A total of 16 patients were enrolled, who had persistent pulmonary lesions including cavity (diameter >2.0 cm) or mass with a history of IPA prior to allo-HSCT in Nanfang Hospital of Southern Medical University. Ten of the 16 patients underwent thoracoscopic surgery before transplantation, i. e. surgery group, the other 6 patients did not have surgery because of primary underlying diseases (non-complete remission) or multiple lesions i. e. non-surgery group. Secondary prophylactic agents were administrated based on treatment response to initial antigual therapy. The 1-year cumulative and breakthrough rate of IPA, the median time of secondary antifungal prophylaxis (SAP) and overall survival were compared between surgery and non-surgery groups. RESULTS: Within a median follow-up of 364 days after transplantation (range 73 to 400 days). The success rate of SAP was 15/16. The 1-year cumulative and breakthrough IPA were 0 and 0 in surgery group, compared with 3/6 and 1/6 in non-surgery group. The median duration of SAP in surgery group and non-surgery group was 95(74-134)days and 192.5 (56-280)days respectively, which was significantly shorter in surgery group (P=0.017). The overall survival between two groups was 8/10 and 4/6 (P=0.534). No discontinuation of SAP happened in both groups due to drug-related adverse events. CONCLUSIONS: In patients with persistent pulmonary IPA lesions, surgical resection followed by SAP might be effective to reduce breakthrough IPA after transplantation with short duration of prophylaxis.

Treatment of invasive fungal infections in cancer patients-updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.

Successful pneumonectomy for invasive pulmonary aspergillosis and advanced non-small cell-lung cancer.

Aspergillus spp. is a pathogenic fungus in patients with malignancy, immunosuppression or respiratory diseases, and invasive pulmonary aspergillosis (IPA) caused by its infection is an aggressive and often lethal disorder. We report a case of non-small-cell lung cancer (NSCLC) where pneumonectomy concomitantly enabled radical cure of the underlying disease and IPA against which different antifungal drugs had been ineffective. In a patient with locally advanced NSCLC that progressed despite chemoradiation, radiation pneumonitis and subsequently cavitary disease developed following the administration of corticosteroids. Based upon the isolation of Aspergillus spp. from sputum, a diagnosis of IPA was made and since the latter was refractory to multiple antifungal drugs, pneumonectomy was undertaken which resulted in successful treatment of both NSCLC and IPA. Surgical intervention should be considered as a therapeutic option for IPA complicating NSCLC that is refractory to medical management.

A rare case of allergic bronchopulmonary mycosis caused by Alternaria alternata.

A rare case of allergic bronchopulmonary mycosis (ABPM), caused by Alternaria alternata, is reported in an immunocompetent resident of Delhi. Her complaints included a generalized, urticarial skin rash and occasional pain in the right lower chest. Her differential count showed eosinophils, 22%; absolute eosinophil count (AEC), 2400 cells/µl; and total IgE, 4007 IU/ml. The computerised tomogram (CT) scan of her thorax showed an enhancing lesion with surrounding ground glass haziness in the right lower lobe. Histopathologic examination of the resected lung revealed a necrotizing granulomatous inflammation, parenchymal infiltration by eosinophils, lymphocytes, neutrophils, plasma cells and some exudative bronchiolitis suggestive of ABPM. Observation of KOH wet mounts of repeat sputum and BAL samples demonstrated the presence of septate, brownish hyphae and cultures of these specimens yielded A. alternata (identified by sequencing of the ITS region). Her serum showed a three-fold higher specific IgE to A. alternata antigens than control levels, and the type I cutaneous hypersensitivity response to antigens of A. alternata was strongly positive. She was treated successfully with oral glucocorticoids and itraconazole. To our knowledge, ABPM due to Alternaria alternata has not been reported previously.

[Invasive pulmonary aspergillosis with hemoptysis; a resected case whose bleeding point is detected pathologically].

A 55-year-old man, who presented with recurrent episodes of hemoptysis, was referred to our hospital under the diagnosis of invasive aspergillosis with a cavity in the right lung. Computed tomography showed a large thick-walled cavity in the right upper lung. He underwent right upper lobectomy. Pathological findings showed a large cavity in right upper lobe. Aspergillus was found in the cavity. A pseudoaneurysm, which was thought to be a cause of hemoptysis, originated from a ruptured pulmonary artery and protruded into the cavity. Hemoptysis is well-known symptom in aspergillosis patients, and surgery for aspergillosis with hemoptysis is sometimes performed. But it is very rare that bleeding point is detected microscopically.

Rare form of semi-invasive aspergillosis in immunocompetent patient: case report.

Chronic necrotizing or semi-invasive aspergillosis represents a disease commonly occurred in patients with mild immunodeficiency. We report a case of chronic necrotizing pulmonary aspergillosis in immunocompetent patient without underlying disease. The discovery of the disease was made accidentally, by finding a nodular opacity on a routine chest X-ray. The diagnostic was confirmed by pathological and bacteriological examination. With specific antifungal treatment, no complete eradication was obtained and the patient has a slow evolution with many relapses.

Video-assisted thoracoscopic lobectomy for pulmonary aspergilloma after life-threatening hemoptysis in a patient with lupus.

Open thoracotomy procedures serve as the mainstay for surgical resection of pulmonary aspergilloma. These procedures are considered among the most challenging for thoracic surgeons, and postoperative morbidity and mortality rates are high. Here, we present patient who underwent video-assisted thoracoscopic lobectomy for aspergilloma. Based on the success of the operation, we suggest that video-assisted thoracoscopic surgical resection be considered as an option for pulmonary aspergilloma.

Use of video-assisted thoracoscopy surgery for the treatment of Aspergillus empyema with bronchopleural fistula.

Pulmonary aspergillus empyema with bronchopleural fistula is a rare and severe disease with a poor prognosis. In this report, we describe the successful surgical treatment of this condition in a 34-year-old man who was initially hospitalized due to complications of chronic hepatitis B. While under artificial liver therapy and as a consequence of long-term corticosteroid use, the patient developed invasive pulmonary aspergillosis, which was further complicated by an empyema and a bronchopleural fistula.Video-assisted thoracoscopy surgery was performed following failure of the prescribed antifungal treatment and chest tube drainage, and the empyema resolved completely 3 months postoperatively,with no evidence of recurrence after 5 months' follow-up.