Early Invasive Pulmonary Aspergillosis Research Articles

Improved diagnostic markers for invasive pulmonary aspergillosis in COPD patients.

The prevalence of invasive pulmonary aspergillosis (IPA) among patients with chronic obstructive pulmonary disease (COPD) is steadily increasing, leading to high mortality. Although early diagnosis can significantly reduce mortality, the efficacy of current diagnostic methods is limited. Consequently, there is a need for novel approaches for early IPA detection. This retrospective study involved 383 hospitalized COPD patients with GOLD stages III and IV. The IPA group (67 patients) and non-IPA group (316 patients) were identified at the First Affiliated Hospital of Guangzhou Medical University between January 2016 and February 2022. We analyzed common serological indicators in our hospital to identify predictive indicators for the early diagnosis of IPA in COPD patients. The sensitivity and specificity of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), lactate dehydrogenase (LDH), and ceruloplasmin (CER) for diagnosing IPA in COPD patients were as follows: CRP (91.2%, 57.7%), ESR (77.5%, 73.0%), PCT (60.5%, 71.4%), LDH (50.0%, 88.8%), and CER (60.7%, 74.3%). Combinations of biomarkers, such as CRP-ESR, CRP-LDH, ESR-LDH, ESR-CER, and LDH-CER, showed promising diagnostic potential, with larger area under the curve (AUC) values for IPA diagnosis in COPD patients. However, no statistically significant difference was observed between the diagnostic efficacy of single biomarkers and combined biomarkers. Notably, compared to those in the unassisted ventilation group, the patients in the assisted ventilation group (including noninvasive ventilation and tracheal intubation/incision-assisted ventilation group) exhibited significantly greater PCT and LDH levels, while the CER significantly decreased (p=0.021). There were no significant differences in biomarker levels between the ICU group and the non-ICU group. CRP (p<0.01), ESR (p=0.028), PCT (p<0.01), and CER (p<0.01) were positively correlated with hospitalization duration, whereas LDH was not correlated with hospitalization duration. Our study highlights the diagnostic potential of CRP, ESR, PCT, LDH, and CER for IPA in COPD patients. CRP and LDH can also initially predict the need for assisted ventilation, while CRP can initially estimate the length of hospitalization. This study represents the first report of the potential of CER for diagnosing IPA, suggesting its significance for further research.

Association between early diagnosis of and inpatient mortality from invasive pulmonary aspergillosis among patients without immunocompromised host factors: a nationwide observational study

The incidence of invasive pulmonary aspergillosis (IPA) among patients without immunocompromised host factors (ICHF) has been described extensively. However, its diagnosis remains challenging. To date, no study has statistically confirmed the efficacy of early IPA diagnosis in patients without ICHF. We conducted a cross-sectional study on mortality from IPA among patients without ICHF, using the Japanese Diagnosis Procedure Combination National Inpatient Database (April 2014-March 2018). The early diagnosis group was defined according to antifungal therapy initiation within 7 days of hospital admission. The delayed diagnosis group was defined according to antifungal therapy initiation between 8 and 28 days of the hospitalization. Associations were estimated using multivariate logistic regression. A total of 423 patients were registered (early diagnosis group, n=262, 62%). The early diagnosis group had a lower mortality rate (30%) than the delayed diagnosis group (42%). The early diagnosis group that was treated with voriconazole was associated with lower odds of mortality (odds ratio 0.55, 95% confidence interval 0.31-0.99, P=0.047). An age of ≥65 years and mechanical ventilation were associated with a higher mortality rate. Early diagnosis along with optimal antifungal treatment are crucial for achieving favorable outcomes among patients with IPA without ICHF.

Utility of serum Galactomannan in diagnosing COVID-19 patients with suspected IPA: an observational study in resource limited settings.

To study the utility of Galactomannan (GM) antigen as a screening marker for diagnosing invasive pulmonary aspergillosis (IPA) in coronavirus disease 2019 (COVID-19) patients. The serum samples from patients with severe COVID-19 diseases admitted to the Critical Care Unit were collected on the 5th day of admission for GM screening. The samples were analysed by enzyme linked immune sorbent assay (ELISA) and GM index of more than 1 was considered as positive. All GM positive patients were serially followed until discharge or death. The GM was raised in serum of 12 out of 38 patients, indicating an incidence of possible COVID-19 associated IPA (CAPA) in 31.57% of patients. The median age of these CAPA patients was 56.5 years, males were significantly more affected than females. The inflammatory marker serum ferritin was raised in all 12 patients (median value of 713.74 ng/ml), while IL-6 was raised in 9 patients (median value of 54.13 ng/ml). None of these patients received antifungals. Their median length of hospital stay was 20 days (IQR: 12, 34 days). All these patients succumbed to the illness. The serum GM appears to be sensitive diagnostic tool to identify early IPA in COVID-19 patients and pre-emptive antifungal therapy could play a role in salvaging these patients.

Invasive pulmonary aspergillosis after heart transplantation

Objective: to assess the incidence, determine the peculiarities of the course of invasive pulmonary aspergillosis (IPA) and identify risk factors for IPA in heart transplant recipients.Materials and methods. From January 2010 to December 2019, 137 heart transplantations (HT) were performed: mean age 46 ± 14 years; male 102 (74%) and female 35 (26%). All patients received a three-component immunosuppressive therapy: calcineurin inhibitors, mycophenolate mofetil (MMF) and Glucocorticoid (GCs). Induction therapy consisted of Basiliximab (81%, n = 111) and antithymocyte immunoglobulin (15%, n = 20). A retrospective analysis of patients with identified post-HT invasive IPA was performed; risk factors for IPA were assessed. In patients with early IPA, the length of stay in the intensive care unit (ICU), the duration of mechanical ventilation, and the initial severity of the condition were studied. All patients with suspected pneumonia underwent bronchoscopy with examination of bronchoalveolar lavage (BAL) and chest computed tomography (chest CT scan).Results. During the follow-up, there were 58 episodes of pneumonia, of which 16 (28%) were IPA (age 33 to 64 years). All patients had a target level of immunosuppressive drugs concentration in blood; basiliximab was used as induction therapy in 15 of 16 patients. Half of the recipients developed IPA in the early post-HT period (less than 3 months after HT), in the rest (n = 8) – at a later date (3 months to 1 year after HT). The diagnosis was verified: 14 out of 16 patients showed an increase in the Aspergillus antigen positivity in the BAL to 7.2 (2.8 ± 1.6); chest CT scan revealed specific changes. In two patients, there were no diagnostic criteria for IPA, but the diagnosis was made based on the results of histological examination after resection of the left lower lobe of the lung. All patients received voriconazole therapy for 2 to 6 months, their immunosuppressive therapy was adjusted (tacrolimus and MMF dose adjustment) and their white blood cell count was monitored. Complete cure of the disease was achieved in 13 (81%) patients. Two patients died within 30 days after HT in the intensive care unit, one died from urogenital diseases caused by bacterial flora and leading to urosepsis, 4 months after IPA treatment was initiated. All patients had risk factors for IPA: taking immunosuppression, including GCs (n = 16), prolonged ICU stay (n = 14), inotropic support exceeding 2 days in the early post-transplant period (n = 10), cachexia during HT (n = 6), leukopenia (n = 9) and neutropenia (n = 14).Conclusion. In heart transplantat recipients, the incidence of IPA among respiratory tract infections is 28%. The risk of developing IPA was highest during the first year following HT. In the majority of recipients, the disease was detected at the early stages; diagnosis required surgical intervention in 12% of cases. A decrease in the risk of developing IPA was associated with correction of the following risk factors for this disease in all patients: volume of immunosuppressive therapy during the first year after transplantation and prevention of the development of neutropenia as a marker of infectious complications or immunosuppression overdose. Early diagnosis of IPA allowed for initiation of timely specific therapy in most recipients and achievement of a positive effect in 80% of them.

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

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

Detection of Airway Colonization by Aspergillus fumigatus by Use of Electronic Nose Technology in Patients with Cystic Fibrosis.

Currently, there is no noninvasive test that can reliably diagnose early invasive pulmonary aspergillosis (IA). An electronic nose (eNose) can discriminate various lung diseases through an analysis of exhaled volatile organic compounds. We recently published a proof-of-principle study showing that patients with prolonged chemotherapy-induced neutropenia and IA have a distinct exhaled breath profile (or breathprint) that can be discriminated with an eNose. An eNose is cheap and noninvasive, and it yields results within minutes. We determined whether Aspergillus fumigatus colonization may also be detected with an eNose in cystic fibrosis (CF) patients. Exhaled breath samples of 27 CF patients were analyzed with a Cyranose 320. Culture of sputum samples defined the A. fumigatus colonization status. eNose data were classified using canonical discriminant analysis after principal component reduction. Our primary outcome was cross-validated accuracy, defined as the percentage of correctly classified subjects using the leave-one-out method. The P value was calculated by the generation of 100,000 random alternative classifications. Nine of the 27 subjects were colonized by A. fumigatus. In total, 3 subjects were misclassified, resulting in a cross-validated accuracy of the Cyranose detecting IA of 89% (P = 0.004; sensitivity, 78%; specificity, 94%). Receiver operating characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.89. The results indicate that A. fumigatus colonization leads to a distinctive breathprint in CF patients. The present proof-of-concept data merit external validation and monitoring studies.

The accuracy of serum galactomannan assay in diagnosing invasive pulmonary aspergillosis.

Galactomannan (GM) antigen is an aspergillus specific antigen that is released during the growth phase of invasive aspergillosis. We aimed to find the optimum cutoff and accuracy of serum Galactomannan assay in immunocompromised patients. Immunocompromised patients diagnosed with invasive pulmonary aspergillosis (IPA) based on the European Organization for Research and Treatment of Cancer/Invasive Mycosis Study Group (EORTC/MSG) with three levels of certainty proven, probable and possible, referred for GM antigen measurement at Immunology, Asthma and Allergy Research Institute (IAARI) from 2006 to 2009 and if they met the criteria were enrolled in this study. Totally 49 patients with IPA were enrolled in our study. According to EORTC/MSG, patients categorized into three levels of certainty: They were diagnosed as 'proven' invasive pulmonary aspergillosis 16(32.7%), 'probable' 18(36.7%) and 'possible' 15(30.6%). The most common host risk factor was solid tumors 17(34.7%). The accuracy of Galactomannan assay increased from 0.5 to 2 cutoffs. The optimum sensitivity and specificity obtained at the index cutoff of ≥1.5 for diagnosis of "proven" IPA; which were respectively, 69.2% and 72.2%. Other cutoffs had high variance between sensitivity and specificity for diagnosis of IPA. The calculated cutoff gained by receiver operating characteristic (ROC) analysis for detecting proven IPA was 1.5. Intermediate accuracy of serum GM test in conjunct with clinical findings would help early IPA detection among immunocompromised patients.

The Initial 96 Hours of Invasive Pulmonary Aspergillosis: Histopathology, Comparative Kinetics of Galactomannan and (1→3)-β- d -Glucan, and Consequences of Delayed Antifungal Therapy

Acute invasive pulmonary aspergillosis is a rapidly progressive and frequently lethal infection. Relatively little is known about early events in the pathogenesis and relationship between the cell wall biomarkers galactomannan and (1→3)-β-d-glucan. The consequences of delayed antifungal therapy are also poorly defined. A persistently neutropenic rabbit model of invasive pulmonary aspergillosis was used to describe the histopathology of early invasive pulmonary aspergillosis and the kinetics of galactomannan and (1→3)-β-d-glucan. The time course of both molecules was mathematically modeled by using a population methodology, and Monte Carlo simulations were performed. The effect of progressive delay in the administration of amphotericin B deoxycholate 1 mg/kg at 24, 48, 72, and 96 h postinoculation on fungal burden, lung weight, pulmonary infarct score, and survival was determined. Histopathology showed phagocytosis of conidia by pulmonary alveolar macrophages at 4 h postinoculation. At 12 to 24 h, there was a progressive focal inflammatory response with conidial germination and hyphal extension. Subsequently, hyphae invaded into the contiguous lung. Galactomannan and (1→3)-β-d-glucan had similar trajectories, and both exhibited considerable interindividual variability, which was reflected in Monte Carlo simulations. Concentrations of both molecules began to rise <24 h postinoculation before pulmonary hemorrhagic infarction was present. Delays of 72 and 96 h in the administration of amphotericin B resulted in fungal burdens and lung weights that were indistinguishable from those of controls, respectively. Galactomannan and (1→3)-β-d-glucan have similar kinetics and are comparable biomarkers of early invasive pulmonary aspergillosis. Antifungal treatment at ≥48 h postinoculation is associated with suboptimal therapeutic outcomes.

Radiological findings of early invasive pulmonary aspergillosis in immune‐compromised patients

Data on the radiological features of invasive pulmonary aspergillosis (IPA) in early stages is scanty. Detection of Aspergillus (ASP) species in broncho-alveolar (BAL) fluid by polymerase chain reaction (PCR) enables early diagnosis of IPA. This study describes the radiological features of early stages of IPA. Chest computerized tomography (CT) films of 22 consecutive immune-compromised patients with IPA diagnosed with the aid of ASP PCR testing from BAL fluid were characterized and compared to that of 18 similar patients diagnosed with traditional bacteriological methods and to data from the literature. It was found that patients diagnosed with the aid of ASP PCR testing tended to have focal disease as manifested by more 11-30 mm nodules with halo (68% vs. 33%, p = 0.04), more focal ground glass (single area 32% vs. 6%, p = 0.05, patchy 32% vs. 0%, p = 0.01) and less diffuse ground glass (0% vs. 22%, p = 0.03), less cavitations (5% vs. 28%, p = 0.05) and less consolidations (segmental 14% vs. 50%, p = 0.02 and diffuse 14% vs. 67%, p = 0.001). It was concluded that the radiological appearance of early IPA diagnosed with the aid of PCR testing included mainly discrete small nodules with halo and focal ground glass, representing the early stage of the disease.

Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin

At present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA). However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentration-time curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.

Pathogenesis ofAspergillus fumigatusand the Kinetics of Galactomannan in an In Vitro Model of Early Invasive Pulmonary Aspergillosis: Implications for Antifungal Therapy

Little is known about the pathogenesis of invasive pulmonary aspergillosis and the relationship between the kinetics of diagnostic markers and the outcome of antifungal therapy. An in vitro model of the human alveolus, consisting of a bilayer of human alveolar epithelial and endothelial cells, was developed. An Aspergillus fumigatus strain expressing green fluorescent protein was used. Invasion of the cell bilayer was studied using confocal and electron microscopy. The kinetics of culture, polymerase chain reaction, and galactomannan were determined. Galactomannan was used to measure the antifungal effect of macrophages and amphotericin B. A mathematical model was developed, and results were bridged to humans. A. fumigatus penetrated the cellular bilayer 14-16 h after inoculation. Galactomannan levels were inextricably tied to fungal invasion and were a robust measure of the antifungal effect of macrophages and amphotericin B. Neither amphotericin nor macrophages alone was able to suppress the growth of A. fumigatus; rather, the combination was required. Monte Carlo simulations showed that human dosages of amphotericin B of at least 0.6 mg/kg were required to achieve adequate drug exposure. This model provides a strategy by which relationships among pathogenesis, immunological effectors, and antifungal drug therapy for invasive pulmonary aspergillosis may be further understood.

Empiric or Presumptive Anti-Aspergillus Treatments for Allogeneic Hematopoietic Stem Cell Transplant Recipients with Sustained Febrile Neutropenia.

Background: Although the onset of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation (HSCT) was bimodal, IPA early after HSCT has become less frequent, partly due to the shortening of neutropenic periods by the use of peripheral blood stem cells or colony-stimulating factors. Therefore, the validity of empiric anti-Aspergillus treatments based on sustained febrile neutropenia according to the IDSA guideline should be re-evaluated.Patients and Methods: We retrospectively reviewed the clinical records of 114 adult patients who underwent allogeneic HSCT between September 2002 and December 2005 in HEPA-filtered clean rooms at the University of Tokyo Hospital. Fluconazole at 200 mg/day was given as anti-Candida prophylaxis. In general, anti-Aspergillus agents were not started empirically, but presumptively started after the detection of positive Aspergillus antigen, positive beta-D-glucan, halo-sign on chest X-ray or CT-scan, and so on, associated with sustained febrile neutropenia. For the definition of early IPA, we employed proven or probable IPA according to the EORTC/MSG criteria that developed between the day of HSCT and seven days after engraftment.Results: All but two who experienced early death showed neutrophil engraftment at a median of 16.5 days after HSCT. Although 15 patients developed IPA after HSCT, early IPA was observed only in 2 (1.8 %) patients. Among 73 patients who experienced sustained febrile neutropenia for more than 7 days before engraftment, we empirically started anti-Aspergillus agents in 13 patients a median of 9 days after the development of febrile neutropenia, whereas fluconazole was continued in 60 patients who had febrile neutropenia for 15 days in median. Four of the 60 patients received presumptive anti-Aspergillus therapy, one of whom developed probable IPA after the initiation of treatment. There was another patient who received anti-Aspergillus treatment only after the development of probable IPA because he showed no prior signs for presumptive therapy. There was no difference in the incidence of early IPA between patients who received empiric anti-Aspergillus therapy and those who did not (0% vs. 3.3%, P>0.99). The two patients who developed early probable IPA were successfully treated with anti-Aspergillus agents.Conclusions: These findings throw doubt on the validity of empiric anti-Aspergillus treatments for allogeneic HSCT recipients with sustained febrile neutropenia, provided that they are treated in clean units with anti-Candida prophylaxis. A randomized controlled trial is warranted to compare empiric and presumptive anti-Aspergillus treatments for allogeneic HSCT recipients with sustained febrile neutropenia.

The radiological spectrum of pulmonary aspergillosis

Imaging findings in the pulmonary aspergilloses can answer important clinical questions. Steroid-responsive chronic asthma due to allergic bronchopulmonary aspergillosis can be differentiated from simple asthma by computed tomography (CT) evidence of extensive and severe central bronchiectasis, mucoid impaction, or small airways lesions. The simple aspergilloma can be differentiated from the complex aspergilloma by the absence of: constitutional symptoms, para-cystic lung opacities, cyst expansion, or progressive pleural thickening. The CT halo sign is a transient finding that can provide a probable diagnosis of early invasive pulmonary aspergillosis in patients who are at extraordinarily high risk of the infection. Patients with a halo sign at baseline are more likely to have a satisfactory treatment response than those without this indicator.

Invasive pulmonale Aspergillose: Radiologische und kernspintomographische Charakteristika

46 patients with invasive pulmonary aspergillosis (IPA) were investigated by chest radiographs (n = 46), plain film tomograms (n = 16), CT (n = 8) and MRI (n = 13). Radiologic characteristics of early IPA were nodular or patchy infiltrates in the upper lobes of all patients. Enlargement of the infiltrates and/or development of segmental/lobar consolidations were typical for fully developing IPA. Air crescent signs were seen in 40% of patients during or after bone marrow restitution. CT added additional information by visualisation of small pleural based infiltrates, demonstration of air crescents and identification of halo phenomena. MRI revealed the target character of nodular aspergillomas with hypointense centres and rims of higher signal intensity. A gadolinium-DTPA rim enhancement could be observed in almost all nodular lesions. Hyperintense areas in nodular and segmental infiltrates on T1-weighted images were interpreted as aging haemorrhage (methemoglobin) in aspergillus-induced haemorrhagic infarcts or in focal parenchymal bleeding.