Damping excessive viral-induced IFN-γ rescues the impaired anti-Aspergillus host immune response in influenza-associated pulmonary aspergillosis.

BACKGROUND: Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection in critically ill influenza patients that is of incompletely understood pathogenesis. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain unacceptably high. We aimed to unravel the IAPA immunopathogenesis as a means to develop adjunctive immunomodulatory therapies. METHODS: We used a murine model of IAPA to investigate how influenza predisposes to the development of invasive pulmonary aspergillosis. Immunocompetent mice were challenged with an intranasal instillation of influenza on day 0 followed by an orotracheal inoculation with Aspergillus 4 days later. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (µCT) and fungal burden with bioluminescence imaging (BLI). At endpoint, high parameter immunophenotyping, spatial transcriptomics, histopathology, dynamic phagosome biogenesis assays with live imaging, immunofluorescence staining, specialized functional phagocytosis and killing assays were performed. FINDINGS: We uncovered an early exuberant influenza-induced interferon-gamma (IFN-γ) production as the major driver of immunopathology in IAPA and delineated the molecular mechanisms. Specifically, excessive IFN-γ production resulted in a defective Th17-immune response, depletion of macrophages, and impaired killing of Aspergillus conidia by macrophages due to the inhibition of NADPH oxidase-dependent activation of LC3-associated phagocytosis (LAP). Markedly, mice with partial or complete genetic ablation of IFN-γ had a restored Th17-immune response, LAP-dependent mechanism of killing and were fully protected from invasive fungal infection. INTERPRETATION: Together, these results identify exuberant viral induced IFN-γ production as a major driver of immune dysfunction in IAPA, paving the way to explore the use of excessive viral-induced IFN-γ as a biomarker and new immunotherapeutic target in IAPA. FUNDING: This research was funded by the Research Foundation Flanders (FWO), project funding under Grant G053121N to JW, SHB and GVV; G057721N, G0G4820N to GVV; 1506114 N to KL and GVV; KU Leuven internal funds (C24/17/061) to GVV, clinical research funding to JW, Research Foundation Flanders (FWO) aspirant mandate under Grant 1186121N/1186123 N to LS, 11B5520N to FS, 1SF2222N to EV and 11M6922N/11M6924N to SF, travel grants V428023N, K103723N, K217722N to LS. FLvdV was supported by a Vidi grant of the Netherlands Association for Scientific Research. FLvdV, JW, AC and GC were supported by the Europeans Union's Horizon 2020 research and innovation program under grant agreement no 847507 HDM-FUN. AC was also supported by the Fundação para a Ciência e a Tecnologia (FCT), with the references UIDB/50026/2020, UIDP/50026/2020, PTDC/MED-OUT/1112/2021 (https://doi.org/10.54499/PTDC/MED-OUT/1112/2021), and 2022.06674.PTDC (http://doi.org/10.54499/2022.06674.PTDC); and the "la Caixa" Foundation under the agreement LCF/PR/HR22/52420003 (MICROFUN).

Timing of recurrence after treatment of pulmonary TB.

Pulmonary TB (PTB) may recur due to reinfection or relapse after initial successful treatment. Based on microbiologically documented cases, we searched Embase, PubMed, Web of Science, and Medline for PTB recurrence. The timeframe of overall recurrences, relapse, reinfection, and risk factors were assessed. We compared the time to recurrence, relapse, and reinfection from treatment completion and plotted this using Kaplan-Meier curves. This systematic review included 23 articles describing 2,153 PTB recurrences in 75,224 treated people across all continents. Genotyping data to distinguish relapse from reinfection was available for 402 recurrences. The cumulative recurrence percentage was 2.9% over 5 years, and the median time for recurrence was 18 months (95% CI 16.99-19.0). Most recurrences (93%) were in HIV-negative people. Relapse occurred earlier than reinfection at 12 months (95% CI 10.86-13.14) vs 24 months (95% CI 21.61-26.39) (P < 0.001, χ2 59.89). In low TB burden settings, recurrences were mainly caused by relapse (85%), whereas in high-burden settings, relapses comprised 56% of recurrences. Recurrences occurred slightly earlier in HIV-positive patients (P = 0.038, χ2 4.30). The emergence of resistance to one or more first-line anti-TB agents was documented in 40 of 421 cases (9.5%). Early recurrences are mainly relapses, while late recurrences are mainly reinfections.

La TB pulmonaire (TBP) peut récidiver en raison d'une réinfection ou d'une rechute après un premier traitement réussi. En nous basant sur des cas documentés sur le plan microbiologique, nous avons mené une recherche dans les bases de données Embase, PubMed, Web of Science et Medline concernant la récurrence de la TBP. Nous avons évalué le calendrier des récidives globales, des rechutes, des réinfections ainsi que des facteurs de risque associés. De plus, nous avons comparé les délais de récurrence, de rechute et de réinfection à partir de la fin du traitement, en les illustrant à l'aide de courbes de Kaplan-Meier. Cette analyse systématique a examiné 23 études rapportant 2 153 cas de récidive de TBP parmi 75 224 individus traités à l'échelle mondiale. Des informations de génotypage permettant de différencier les rechutes des réinfections étaient accessibles pour 402 cas de récidive. Le taux cumulé de récidive s'élevait à 2,9% sur une période de 5 ans, avec un délai médian de récidive de 18 mois (IC à 95% 16,99­19,0). La majorité des récidives (93%) concernait des individus séronégatifs. Les rechutes se sont produites plus rapidement que les réinfections, à 12 mois (IC 95% 10,86­13,14) contre 24 mois (IC 95% 21,61­26,39 ; P < 0,001 ; χ2 59,89). Dans les environnements où le fardeau de la TB est faible, les récidives étaient principalement attribuées à des rechutes (85%), tandis que dans les contextes à fardeau élevé, les rechutes représentaient 56% des récidives. Les récidives se sont manifestées légèrement plus tôt chez les patients séropositifs (P = 0,038, χ2 4,30). L'apparition d'une résistance à un ou plusieurs médicaments anti-TB de première ligne a été observée dans 40 cas sur 421, soit 9,5%. Les récidives précoces sont majoritairement des rechutes, tandis que les récidives tardives sont principalement dues à des réinfections.

Diagnostic value and clinical use of metagenomic next-generation sequencing for invasive pulmonary aspergillosis.

OBJECTIVE: To compare the diagnostic efficacy of metagenomic next generation sequencing (mNGS) with traditional fungal culture, (1,3)-ß-D glucan (G) test, and galactomannan (GM) test in diagnosing invasive pulmonary aspergillosis (IPA) and to explore the advantages and disadvantages of mNGS for IPA diagnosis. METHODS: A retrospective analysis was conducted on 136 patients admitted to the Department of Respiratory and Critical Care Medicine of Affiliated Hospital of Putian University from March 2018 to March 2020. Among them, there were 66 patients with IPA (IPA group) and 70 without (non-IPA group). Baseline data, inflammatory factors, cytokines, and specimens such as bronchoalveolar lavage fluid (BALF) and blood of these patients were collected. Fungal culture test, G test, GM test and mNGS test were performed. Information included for analysis encompassed patients' host factors, clinical features, chest scanning images, laboratory test results, and treatment outcome. RESULTS: There was no statistical difference in the baseline data or inflammatory factors in patients between the IPA group and the non-IPA group. Further analysis showed that the sensitivity of mNGS in diagnosing IPA was 53.03%, which was higher than that of traditional fungal culture test (27.27%), G test (31.82%), and GM test (34.85%). Notably, when combining fungal culture, G test, GM test, and mNGS, the sensitivity increased to 69.70%, with a specificity of 97.14%. The sensitivity of the combined test was higher than that any of the tests alone for diagnosing IPA. CONCLUSION: mNGS test offers superior diagnostic performance for IPA in comparison to traditional tests, particularly for testing samples like bronchoalveolar lavage fluid and bronchial secretions. The test result remains valuable even after aspergillus treatment. In addition, the use of mNGS in conjunction with other traditional tests, such as fungal culture test, G test, and GM test, can enhance the diagnostic efficacy for IPA.

Epidemiology of chronic pulmonary aspergillosis: A nationwide descriptive study.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) has recently gained attention owing to its substantial health burden. However, the precise epidemiology and prognosis of the disease are still unclear due to the lack of a nationwide descriptive analysis. This study aimed to elucidate the epidemiology of patients with CPA and to investigate their prognosis. METHODS: Using a national administrative database covering >99% of the population in Japan, we calculated the nationwide incidence and prevalence of CPA from 2016 to 2022. Additionally, we clarified the survival rate of patients diagnosed with CPA and identified independent prognostic factors using multivariate Cox proportional hazard analysis. RESULTS: During the study period, while the prevalence of CPA remained stable at 9.0-9.5 per 100,000 persons, its incidence declined to 2.1 from 3.5 per 100,000 person-years. The 1-, 3-, and 5-year survival rates were 65%, 48%, and 41%, respectively. During the year of CPA onset, approximately 50% of patients received oral corticosteroids (OCS) at least once, while about 30% underwent frequent OCS treatment (≥4 times per year) within the same timeframe. Increased mortality was independently associated with older age (>65 years) (hazard ratio [HR], 2.65; 95% confidence interval (CI), 2.54-2.77), males (1.24; 1.20-1.29), a history of chronic obstructive pulmonary disease (1.05; 1.02-1.09), lung cancer (1.12; 1.06-1.18); and ILD (1.19; 1.14-1.24); and frequent OCS use (1.13; 1.09-1.17). Conversely, decreased mortality was associated with a history of tuberculosis (HR, 0.81; 95% CI, 0.76-0.86), non-tuberculous mycobacteria (0.91; 0.86-0.96), and other chronic pulmonary diseases (0.89; 0.85-0.92). CONCLUSIONS: The incidence of CPA decreased over the past decade, although the prevalence was stable and much higher than that in European countries. Moreover, the patients' prognosis was poor. Physicians should be vigilant about CPA onset in patients with specific high-risk underlying pulmonary conditions.

Clinical characteristics of pulmonary Mycobacterium avium complex disease in patients with interstitial lung disease.

OBJECTIVE: Mycobacterium avium complex pulmonary disease (MAC-PD) is occasionally complicated by interstitial lung disease (ILD) in clinical practice, but clinical studies are limited. This study aims to elucidate the clinical and imaging characteristics of MAC-PD in patients with ILD. METHODS: We retrospectively analyzed imaging and clinical data from medical records of 54 consecutive ILD patients diagnosed with MAC-PD from 2011 to 2021 at our institution. We compared the imaging and clinical data of these patients with 2218 ILD patients diagnosed at our institution. RESULTS: The mean age of the patients was 74 years, with 25 males and 29 females, and a mean body mass index (BMI) of 20.0 kg/m2. Compared to all ILD patients, ILD-associated MAC-PD had older ages, lower BMI. The most common underlying ILD diagnosis was unclassifiable interstitial pneumonia. MAC-PD imaging classification was nodular-bronchiectatic (NB) type in 17 patients, fibro-cavitary (FC) type in 15 patients, and unclassifiable (UC) type in 22 patients. Many UC types were difficult to diagnose due to the absence of clear findings indicative of MAC infection. Chronic pulmonary aspergillosis complication was 24.1 %. The mean survival of ILD-associated MAC-PD was 55.6 months, shorter than that of regular MAC-PD. The UC type had a shorter survival than the NB type, similar to the FC type. CONCLUSION: MAC-PD associated with ILD frequently complicates chronic pulmonary aspergillosis and has a poor prognosis. The most common imaging type, UC type, particularly has a shorter survival. Careful management is essential for MAC-PD associated with ILD.

Investigation of risk factors for invasive pulmonary aspergillosis among patients with COVID-19.

COVID-19 associated pulmonary aspergillosis (CAPA) had been reported, and raised concern about this secondary infection due to the high mortality. This study aimed to investigate the risk factors for CAPA. The enrolled 114 COVID-19 patients were further divided into CAPA group and non-CAPA group. Demographic characteristics, underlying diseases, laboratory parameters and therapeutic schedule between the two groups were compared to identify the independent risk factors for CAPA by univariate analysis and multivariable logistic regression analysis. Sensitivity and specificity of independent risk factors were confirmed by receiver operating characteristic (ROC) curve analysis. Univariate analysis showed that renal transplant, IL-6 and CRP levels, decreased CD4 + T cell and CD8 + T cell, duration of antibiotics therapy, and prolonged mechanical ventilation were risk factors for development of CAPA. These factors were further analyzed by multivariable logistic regression analysis and the results indicated that elevated IL-6 level, decreased CD4 + T cell and prolonged mechanical ventilation could be recognized as independent risk factors for CAPA in COVID-19 patients. Identification of these risk factors is essential to initiate antifungal therapy as soon as possible to improve outcome of patients with CAPA.

High-Dose Corticosteroid Use in Severe to Critically Ill Patients With COVID-19: A Nationwide Population-Based Matched Cohort Study.

BACKGROUND: Systemic corticosteroids have become the standard of care for severe to critically ill patients with coronavirus disease 2019 (COVID-19). However, the real-world efficacy and safety outcomes associated with a higher dose of corticosteroids remain uncertain. METHODS: We conducted a nationwide, population-based, matched cohort study of severe to critically ill adult patients with COVID-19 between January 2020 and June 2021 in Korea using the National Health Information Database. Patients using systemic corticosteroids were included and high-dose corticosteroid use was defined as a daily mean prescribed dose of more than 6 mg of dexamethasone. We then employed a proportional hazard regression model to identify prognostic factors for 28-day all-cause mortality and conducted a Fine and Gray regression model to assess risk factors for developing COVID-19-associated pulmonary aspergillosis (CAPA). RESULTS: During the study period, 102,304 patients with COVID-19 were screened, 5,754 met the eligibility criteria, and 2,138 were successfully matched. The mean prescribed daily dose was 4.2 mg and 13.4 mg in the standard- and high-dose groups, respectively, and the mean duration of use was not different between the groups. High-dose corticosteroid use independently increased all-cause mortality at 28 days (adjusted hazard ratio [aHR], 1.48; 95% confidence interval [CI], 1.25-1.76) and 90 days (aHR, 1.63; CI, 1.44-1.85) after admission. Subgroup analysis revealed a statistically significant elevation in the risk of mortality among patients using low-flow or high-flow nasal cannulas, with aHRs of 1.41 and 1.46, respectively. No significant impact of high-dose steroids was observed, even in patients who underwent mechanical ventilation at 28 days (aHR, 1.17; CI, 0.79-1.72). As a safety outcome, high-dose corticosteroid use showed an association with the development of CAPA (aHR, 2.97; 95% CI, 0.94-9.43). CONCLUSION: Among severe to critically ill patients with COVID-19, high-dose corticosteroid use was associated with increased 28-day all-cause mortality and showed a trend toward the development of CAPA.

Successful treatment of mixed pulmonary Aspergillus and Mucor infection using intrabronchial amphotericin B infusion: a case report and literature review.

BACKGROUND: Reports of pulmonary aspergillosis and mucormycosis co-infections are rare; thus, limited guidance is available on early diagnosis and treatment. We present a case of mixed pulmonary Aspergillus and Mucor infection and review the literature regarding this co-infection. The diagnosis and treatment methods are summarized to improve clinicians' understanding of the disease and to facilitate early diagnosis and treatment. CASE PRESENTATION: A 60-year-old male farmer with poorly controlled diabetes mellitus was admitted to hospital with a fever of unknown origin that had been present for 15 days and pulmonary aspergillosis complicated by Mucor spp. INFECTION: Because multiple lobes were involved, the infection worsened despite surgical resection and antifungal therapy. Finally, we treated this patient with a bronchoscopic infusion of amphotericin B. After four courses of bronchoscopic amphotericin B infusion, we observed rapid clinical improvement and subsequent resolution of pulmonary infiltrates. CONCLUSION: Our case highlights the use of bronchoscopy in the successful clinical treatment of invasive fungal diseases of the lung.

Invasive Mediastinal Aspergillosis in an 18-Year-Old Immunocompetent Female Leading to Stroke.

We present a case of invasive pulmonary aspergillosis in an immunocompetent young female. An 18-year-old female presented with symptoms of a left-sided middle cerebral artery (MCA) stroke with right arm weakness and aphasia. Computed tomography (CT) brain confirmed the diagnosis of stroke. Further history revealed that the patient had been experiencing low-grade fevers with occasional shortness of breath for the past year. The blood work had eosinophilia at that time for which she was given mebendazole but saw little improvement. Chest X-rays showed upper lobe consolidation for which a tuberculosis (TB) workup was also done, which also came out negative. At the current presentation, she underwent further workup with echocardiography and eventual ultrasound-guided mediastinal biopsy that ultimately led to the correct diagnosis of aspergillosis. However, sadly, it was already too late for the patient who passed away one day after the commencement of the amphotericin B therapy. This paper hopes to decrease the threshold of clinical suspicion for invasive aspergillosis (IA) regardless of the immunity status of the patient, especially if they are presenting with an unrelenting mediastinal or pulmonary symptom complex in the setting of eosinophilia.

Retrospective Comparison of Two Aspergillus IgG Enzyme Immunoassays for Diagnosing Pulmonary Aspergillosis.

Aspergillus-specific antibodies are diagnostic indicators of allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). Tests for detecting Aspergillus-specific antibodies were not used clinically in Japan, and the production of the Aspergillus precipitin test was discontinued. Thus, alternative tests for diagnosing aspergillosis are urgently needed. We retrospectively evaluated 64 patients with suspected ABPA and CPA who underwent precipitin antibody testing. Serum Aspergillus IgG levels were measured and compared using the Bordier Aspergillus fumigatus ELISA and the Platelia Aspergillus IgG (Bio-Rad) kits. Of the participants, 18 were diagnosed with CPA, and 8 were diagnosed with ABPA. Both the Bordier and Bio-Rad kits showed high sensitivity and specificity for CPA and ABPA. The area under the receiver operating characteristic curves for the Bordier and Bio-Rad kits were 0.97 and 0.95, respectively, for CPA, and 0.89 and 0.91, respectively, for ABPA. In contrast to the Bordier kit, the Bio-Rad kit showed relatively low anti-Aspergillus IgG levels and lower sensitivity to non-fumigatus Aspergillus infections. The Aspergillus-specific IgG ELISA tests showed sufficient diagnostic accuracy. Therefore, these assays are recommended as alternatives to the precipitin kit for diagnosing aspergillosis in clinical settings in Japan.

Optimized Antifungal Therapy for Chronic Pulmonary Aspergillosis.

Chronic pulmonary aspergillosis (CPA) represents a spectrum of lung disorders caused by local proliferation of Aspergillus hyphae in individuals with non-systemic or mildly systemic immunodepression or altered pulmonary integrity due to underlying disease. While long-term systemic antifungal treatment is still the mainstay for management, surgery is considered mainly in rarer invasive disease manifestations such as sinusitis and osteomyelitis. Optimal application of existing antifungal agents with suitable pharmacokinetic properties is important for the treatment of diseases such as CPA, which requires long-term use. Appropriate management of side effects by therapeutic drug monitoring, maintenance of adherence, and assessment of drug resistance to Aspergillus can provide safe and effective treatment in the future. Most available antifungal agents for the management of mycoses in humans have disadvantages that can limit their use in clinical practice. By contrast, second generation antifungals such as triazoles have advantages of extended antifungal spectrum and availability in both oral and intravenous formulations. Isavuconazole, a new extended spectrum triazole, has been shown to be effective against Aspergillus. The safety profile and excellent pharmacokinetic characteristics of isavuconazole make it an attractive option for treatment of invasive fungal infections including CPA. With this drug now available in Japan, new evidence is expected to expand treatment options. This review focuses on the selection of antifungal agents based on national and international guidelines and the characteristics of each agent for their appropriate use in CPA.

Evaluation of the Dynamiker Quantitative Anti-Aspergillus Fumigatus Specific Detection for the Diagnosis of Different Kinds of Chronic Pulmonary Aspergillosis.

Background: Aspergillus-specific IgG antibody test is considered to be the most reliable method for diagnosing chronic pulmonary aspergillosis (CPA), while its diagnostic roles in different kinds of CPA are still uncertain and it is a challenge of having a threshold to interpret the IgG levels. Purpose: This study aimed to evaluate the diagnostic value of the Dynamiker quantitative Aspergillus fumigatus-specific IgG antibody in different types of CPA with the aim of providing a reference for clinical work. Methods: This prospective study collected the clinical data of patients with suspected CPA admitted to the hospital from January 2020 to December 2022 and divided them into two groups: CPA and non-CPA. The study analyzed clinical characteristics and Aspergillus-specific IgG antibody test's diagnostic value, and a receiver operating characteristic (ROC) curve was used to evaluate diagnostic efficacy. Results: We enrolled 54 CPA patients and 132 non-CPA patients. The average admission age of the CPA group was 61.0 (43.8, 70.0) years, and the sex ratio was 32/22 (male/female). The level of Aspergillus fumigatus-specific IgG antibody in the CPA group was significantly higher than the non-CPA group (95.2 (31.3, 213.3) vs 47.5 (34.0, 80.3) AU/mL, p = 0.001). The area under the ROC curve was 0.653 (95% confidence interval [CI]: 0.580-0.721, p = 0.003). The cutoff with the best diagnostic efficacy was 87 AU/mL, and the sensitivity and specificity were 57.4% and 77.3%, respectively. There was no significant difference in the level of specific IgG antibody among the five CPA types (p = 0.543); however, it was relatively higher in chronic cavitary pulmonary aspergillosis (CCPA). Conclusion: Aspergillus-specific IgG antibody is valuable diagnostic marker for CPA, while its value in differential diagnosis among different types of CPA is limited.

Clinical factors associated with invasive pulmonary aspergillosis in patients with severe fever with thrombocytopenia syndrome: analysis of a 6-year clinical experience.

Background: Invasive pulmonary aspergillosis (IPA) typically occurs in immunocompromised individuals. Severe fever with thrombocytopenia syndrome (SFTS) patients are typically characterized by fever, thrombocytopenia, and leukopenia. These patients typically present with dysregulation of cellular and humoral immunity, which may predispose them to IPA. Our study aimed to identify risk factors for SFTS-associated invasive pulmonary aspergillosis (SAPA) and evaluate its associated prognostic impact. Methods: We conducted a cohort study between January 2017 and December 2022 in a tertiary hospital in Wuhan City, China. All SFTS patients hospitalized in our department who formally consented were divided into a SAPA group and a non-SAPA group according to whether they were coinfected with aspergillosis or not. The independent risk factors for the SAPA group were determined by multivariate logistic regression. Receiver operating characteristic (ROC) analysis was used to assess the statistical value of parameters to predict SAPA patients. The survival analysis was carried out using the Kaplan-Meier (KM) method. Results: Of the 269 hospitalized SFTS patients enrolled in the study, 118 (43.87%) cases were diagnosed with SAPA with an average age of 65.71 ± 9.7 years. Multivariate logistic regression analysis revealed that age, neurological complications, serum severe fever with thrombocytopenia syndrome virus (SFTSV) RNA loads, the white blood cell (WBC) count, platelet (PLT) count, albumin (ALB) and globulin (GLB) concentrations, and cardiac troponin I (cTNI) were complementary risk factors for the development of IPA in SFTS patients. The risk score is calculated as 5 times age, plus 6 times neurological complications, plus 10 times RNA (log), plus 5 times WBC, minus 5 times PLT, minus 5 times ALB, plus 5 times GLB, and plus 6 times cTNI. ROC curve analysis showed that the area under the receiver operating characteristic (AUROC) curve represented a risk score of 0.837 (95% CI: 0.789-0.885, p < 0.001) for predicting IPA in SFTS patients. The average length of hospitalization in the SAPA group was more prolonged than non-SAPA. SAPA and non-SAPA groups had significantly different mortality rates: 25.42% (SAPA) and 3.97% (non-SAPA) (p < 0.05). Conclusion: SFTS patients with IPA have high morbidity and mortality. Early monitoring of neurological complications, SFTSV RNA loads, WBC, PLT, ALB, GLB, and cTNI in SFTS patients may be useful in predicting the occurrence of IPA.

Navigating Uncertainty: Managing Influenza-Associated Invasive Pulmonary Aspergillosis in an Intensive Care Unit.

We present a challenging case of a patient admitted to an intensive care unit with influenza-associated pulmonary aspergillosis (IAPA). The clinical course was characterised by refractory fungal pneumonia and tracheobronchitis, suspected drug-induced liver injury due to triazole antifungals, and secondary bacterial infections with multidrug-resistant microorganisms, resulting in a fatal outcome despite the optimisation of antifungal treatment through therapeutic drug monitoring. This case underscores the complexity that clinicians face in managing critically ill patients with invasive fungal infections.

Invasive pulmonary aspergillosis in patients with acute leukemia.

INTRODUCTION: Invasive pulmonary aspergillosis is a serious complication in hematology. AIM: Describe the prevalence, diagnostic aspects, therapeutic modalities, and evolution of the IPA cases occurring in patients with acute leukemia. METHODS: Our study was retrospective including patients with acute leukemia who developed invasive pulmonary aspergillosis during the period January 2009 and December 2020 at the hematology department in south Tunisia. The IPA was defined in three levels of probability according to the criteria of the EORTC / MSG 2019. RESULTS: We collected 127 patients who presented with Invasive pulmonary aspergillosis. Sixty-three percent of our patients had acute myeloid leukemia. The diagnosis of invasive pulmonary aspergillosis was during the induction course in 76% of cases. Twenty-seven of our patients had chest pain. The chest Computed tomography (CT) scan showed the Halo sign in 89% of cases. The Aspergillus galactomannan antigen was positive in 38% of cases. Extrapulmonary aspergillosis involvement was noted in 18% of cases: IPA was possible and probable respectively in 59% and 41% of cases. All patients treated with Voriconazole with a favorable response in 54% of cases. The mortality rate was 46%. The overall survival at week 12 was 56%. CONCLUSION: The morbidity and mortality of patients who developed invasive pulmonary aspergillosis with acute leukemia in our series were high. We need to improve our strategy for early diagnosis and management.

Drug-drug interactions in the management of non-tuberculous mycobacterial infections.

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a refractory chronic respiratory infectious disease and its prevalence is increasing globally. The standard treatment regimen for NTM-PD involves long-term multidrug therapy including macrolides. The incidence of adverse events is high given the advanced age of many NTM-PD patients. In addition, drug-drug interactions under coexisting conditions add additional complexity. Despite guidelines advocating multidrug therapy for NTM-PD, low adherence rates probably owing to the relatively frequent adverse events and drug interactions. An appropriate treatment regimen can improve the bacteriological response rates, reduce the development of macrolide resistance, and mitigate adverse events. Of particular concern are the interactions arising from new complications that develop with NTM-PD. Notably, chronic pulmonary aspergillosis occasionally co-infects NTM-PD, which can lead to poor prognosis. The primary therapeutic modality for chronic pulmonary aspergillosis is the azoles. However, the interaction with rifamycin is problematic, making it challenging to continue standard treatment for NTM-PD and requiring drug adjustments. The implications of rifamycin extend beyond chronic pulmonary aspergillosis, impacting various other diseases such as those requiring immunosuppressive agents and AIDS patients requiring antiretroviral therapy. Hence, a comprehensive consideration of drug interactions is imperative for the initiation of NTM-PD treatment. This mini-review focuses on drug-drug interactions in a multidrug regimen for NTM-PD and discusses the essential points to be considered in the treatment of NTM.

Invasive Pulmonary Aspergillosis in Patients with HBV-Related Acute on Chronic Liver Failure.

BACKGROUND: We aim to investigate the characteristics of invasive pulmonary aspergillosis (IPA) in patients with HBV-related acute on chronic liver failure (HBV-ACLF). METHODS: A total of 44 patients with probable IPA were selected as the case group, and another 88 patients without lung infections were chosen as the control group. RESULTS: HBV-ACLF patients with probable IPA had more significant 90-day mortality (38.6% vs. 15.9%, p = 0.0022) than those without. The white blood cell (WBC) count was the independent factor attributed to the IPA development [odds ratio (OR) 1.468, p = 0.027]. Respiratory failure was associated with the mortality of HBV-ACLF patients with IPA [OR 26, p = 0.000]. Twenty-seven patients received voriconazole or voriconazole plus as an antifungal treatment. Plasma voriconazole concentration measurements were performed as therapeutic drug monitoring in 55.6% (15/27) of the patients. The drug concentrations exceeded the safe range with a reduced dosage. CONCLUSIONS: The WBC count might be used to monitor patients' progress with HBV-ACLF and IPA. The presence of IPA increases the 90-day mortality of HBV-ACLF patients mainly due to respiratory failure. An optimal voriconazole regimen is needed for such critical patients, and voriconazole should be assessed by closely monitoring blood levels.

IL-17 in plasma and bronchoalveolar lavage fluid in non-neutropenic patients with invasive pulmonary aspergillosis.

Background: The purpose of this study was to investigate the diagnostic value of IL-17 detection in bronchoalveolar lavage fluid (BALF) and plasma samples from nonneutropenic patients with invasive pulmonary aspergillosis. Methods: We retrospectively collected data on non-neutropenic patients who were suspected to have IPA admitted to the Third Affiliated Hospital of Soochow University between March 2020 to January 2023. IL-17 and GM were measured using enzyme-linked immunosorbent assays. Results: A total of 281 patients were enrolled in this study, of which 62 had proven or probable IPA and the remaining 219 patients were controls. The plasma and BALF IL-17 levels were significantly higher in the IPA group compared with the control group. The plasma GM, plasma IL17, BALF GM, and BALF IL17 assays had sensitivities of 56.5%, 72.6%, 68.7%, and 81.2%, respectively, and specificities of 87.7%, 69.4%, 91.9%, and 72.6%, respectively. The sensitivity of IL17 in plasma and BALF was higher than that of GM. Plasma GM in combination with IL-17 increases the sensitivity but does not decrease the diagnostic specificity of GM testing. The diagnostic sensitivity and specificity of BALF GM combined with IL-17 for IPA in non-neutropenic patients were greater than 80% and there was a significant increase in sensitivity compared with BALF GM. Conclusions: Plasma and BALF IL-17 levels were significantly higher in non-neutropenic patients with IPA. The sensitivity of plasma and BLAF IL-17 for diagnosing IPA in non-neutropenic patients was superior to that of GM. Combined detection of lavage fluid GM and IL17 significantly improves the diagnosis of IPA in non-neutropenic patients. The combined detection of GM and IL-17 in plasma also contributes to the diagnosis of IPA in patients who cannot tolerate invasive procedures.

Clinical Features, Treatment Outcome and Potential risk Factors for Recurrence Among Patients with Chronic Pulmonary Aspergillosis in a Resource-limited Setting: A Retrospective Observational Study.

OBJECTIVE: To evaluate the clinical characteristics and treatment outcomes of patients with chronic pulmonary aspergillosis (CPA) and to determine risk factors for disease recurrence. METHODS: A total of 43 patients with CPA (mean ± SD age: 61.4 ± 10.5 years, 83.7% were males) were included in this retrospective study. Data on demographic, clinical and disease-related characteristics, galactomannan (GM) test positivity in bronchoalveolar lavage (BAL) samples, histopathological diagnosis, imaging (CT) findings and CPA forms, antifungal therapy, recurrence rate and time to recurrence were recorded. RESULTS: Chronic obstructive pulmonary disease (COPD;76.7%) was the leading predisposing factor, and the aspergillus nodule (37.2%) was the most prevalent CPA form.GM test positivity was noted in 89.7% (35/39) of BAL samples. Median duration of voriconazole treatment was 180 days. CPA recurrence was noted in 14.0% of patients, while the comorbid tuberculosis sequela (66.7% vs. 16.2%, p = 0.02) and mild immunosuppressive disorder (100.0% vs. 51.4%, p = 0.032) were significantly more common in patients with recurrence vs. those without recurrence. Recurrence rate was 50.0% (3 of 6 patients) in patients with simple aspergilloma, and ranged from 0.0% to 25.0% in those with other CPA forms. Treatment duration and time to recurrence ranged 70-270 days and 1.1-37 months, respectively in simple aspergilloma, while they were ranged 150-180 days and 30-43.3 months, respectively in other CPA forms. CONCLUSIONS: Our findings indicate the importance of considering CPA in differential diagnosis in patients with predisposing conditions, and emphasize the tuberculosis sequela, immunosuppressive disorder and the certain CPA forms managed with shorter duration of antifungal therapy (i.e., simple aspergilloma) as the potential risk factors of CPA recurrence.

Clinical significance of chronic pulmonary aspergillosis in lung cancer patients undergoing anticancer drug therapy.

BACKGROUND: Advances in anticancer drugs for lung cancer (LC) have improved the prognosis of LC. Chronic pulmonary aspergillosis (CPA) is a progressive and often exacerbating respiratory disease with a poor prognosis. To date, the prognosis of LC complicated by CPA has not been elucidated. This study investigated the clinical implications of concomitant CPA in patients with LC undergoing anticancer drug treatment. METHODS: Between January 2010 and May 2020, we consecutively enrolled patients with LC complicated with CPA at five different institutions in Japan. We analyzed patients with LC complicated by CPA who received anticancer drug treatment. RESULTS: A total of 10 patients with LC complicated by CPA received anticancer drug treatment. The median overall survival (OS) was 14.57 months (95% confidence interval [CI]: 5.37-21.67). The cause of death in all patients was LC. Six of the seven patients with LC did not show worsening pulmonary aspergillosis lesions during the anticancer drug treatment. Although two patients discontinued anticancer drug treatment due to pneumonitis, CPA complications did not interfere with the continuation of anticancer drug treatment. In univariate analyses, squamous histology (p = 0.01) and body mass index (<18.5 kg/m2) (p = 0.0008) were significantly associated with poorer OS. CONCLUSIONS: This study demonstrated that the cause of death in LC patients with concomitant CPA who received anticancer drug treatments and effective antifungal treatment was LC progression. Further large-scale studies are needed to identify the effect of CPA in patients with LC.