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.

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.

Coinfection of Klebsiella pneumoniae and Aspergillus in a patient with chronic obstructive pulmonary disease post cardiac arrest: a case report.

INTRODUCTION: Chronic obstructive pulmonary disease is a lung condition characterized by chronic respiratory symptoms (breathlessness, cough, and expectoration). In the advanced stages, patients often report to the Accident & Emergency department due to worsening of symptoms. Because of the repeated exposure to corticosteroids during the management of exacerbations, these patients are susceptible to super additional infections. Pulmonary aspergillosis can be divided into three main categories: invasive pulmonary aspergillosis, allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Aspergillus overlap syndrome is defined as the presence of more than one form of Aspergillus in a single patient. However, coinfection with Klebsiella and pulmonary aspergillosis overlap syndrome is rare and poses a treatment challenge. As per a pub med search, no such case report has been reported in a case of chronic obstructive pulmonary disease. CASE REPORT: We report the case of a 66-year-old male, Punjabi Hindu by ethnicity, who was a reformed smoker with a known case of COPD. He presented with a history of breathlessness (mMRC grade 4) associated with cough with expectoration and wheezing for 15 days and intermittent episodes of hemoptysis for more than 6 months. The examination revealed tachypnea and wheezing throughout the lung fields. He was initially managed with parenteral steroids and frequent nebulization with bronchodilators. On day 5 of hospitalization, the patient experienced worsening of symptoms and cardiac arrest; he was intubated and return of spontaneous circulation was achieved within 5 minutes of cardio pulmonary resuscitation. Tracheal aspirate and culture revealed Aspergillus fumigatus and Klebsiella pneumoniae respectively. He underwent chest CT, which showed features suggestive of allergic bronchopulmonary aspergillosis and invasive pulmonary aspergillosis. He was found to have elevated ß-D-glucan, galactomannan, and aspergillus IgE and IgG. Severe pneumonia and pulmonary Aspergillus overlap syndrome were managed with antibiotics, steroids, and antifungals. Over the next 15-20 days, his general condition improved. He was discharged after 45 days of hospitalization and continued on oral corticosteroids, antifungals, and inhaled bronchodilators. CONCLUSION: Coinfection with bacteria and fungi worsens the outcome. Clinicians should be aware of the polymicrobial manifestations and various drug interactions involved. Timely diagnosis aids in better management strategies and improved patient outcomes.

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.

[Research advances on the mechanism of immune regulation of interferon in Aspergillus infection].

Pulmonary aspergillosis is a serious pulmonary fungal infectious disease. It is difficult to manage and has limited treatment options. Existing anti-aspergillus medications have high rates of treatment failure and increased drug resistance, making it difficult to meet the clinical requirements. Therefore, the development of new, effective treatment programs is critical. According to research, interferons play an important role in the body's immune response to bacterial and viral infectious diseases. Inadequate interferon expression or dysfunction can put the body at risk for certain infectious diseases. Interferon has been used in clinical trials to prevent or treat infectious diseases. In recent years, researchers have focused on the immunological role of interferon in Aspergillus infections and its potential for clinical application. This review summarized the most recent advances in the immunoregulatory mechanisms of interferon and its clinical application in Aspergillus infections.

Chronic Cavitary Pulmonary Aspergillosis: Complication of Pulmonary Tuberculosis.

Pulmonary Aspergillosis is a fungal infection of the lungs that can lead to invasive disease and the formation of cavities, especially in the immunocompromised population. The most common clinical features are no symptoms at all to fever, cough, nondescript chest discomfort, trivial hemoptysis, and shortness of breath. Most patients respond well to Itraconazole therapy. Pulmonary Tuberculosis is one of the conditions that can lead to Aspergillosis, especially in cavities that are formed by Mycobacteria; both often manifest with similar clinical features and lead to diagnostic error. We present a case of a 28-year-old male diagnosed with pulmonary tuberculosis who developed symptoms of persistent cough, hemoptysis, increasing fatigue, and weight loss despite compliance with antitubercular therapy. Ultimately diagnosis of Cavitary pulmonary aspergillosis was made on clinical, laboratory, and radiological grounds. In a patient presenting with worsening symptoms of tuberculosis, there should be a suspicion of aspergillosis, necessitating the performance of standard fungal infection investigations. Keywords: Immunocompromise iosts; lung cavity; pulmonary aspergillosis; tuberculosis.

Inappropriate treatment of pulmonary aspergillosis caused by Aspergillus flavus in susceptible pediatric patients: a case series.

BACKGROUND: Pulmonary aspergillosis is a prevalent opportunistic fungal infection that can lead to mortality in pediatric patients with underlying immunosuppression. Appropriate and timely treatment of pulmonary aspergillosis can play a crucial role in reducing mortality among children admitted with suspected infections. CASE PRESENTATION: The present study reports three cases of inappropriate treatment of pulmonary aspergillosis caused by Aspergillus flavus in two Iranian pediatric patients under investigation and one Afghan patient. Unfortunately, two of them died. The cases involved patients aged 9, 1.5, and 3 years. They had been diagnosed with pulmonary disorders, presenting nonspecific clinical signs and radiographic images suggestive of pneumonia. The identification of A. flavus was confirmed through DNA sequencing of the calmodulin (CaM) region. CONCLUSION: A. flavus was the most prevalent cause of pulmonary aspergillosis in pediatric patients. Early diagnosis and accurate antifungal treatment of pulmonary aspergillosis could be crucial in reducing the mortality rate and also have significant potential for preventing other complications among children. Moreover, antifungal prophylaxis seems to be essential for enhancing survival in these patients.

Pseudomonas and aspergillus symbiotic coinfections in a case of chronic obstructive pulmonary disease and diabetes mellitus.

Coinfection of Pseudomonas and Aspergillus has not been previously reported in patients with chronic obstructive pulmonary disease (COPD). A middle-aged, thinly built woman (Body Mass Index: 18.1 kg/m²) who smokes bidi (a type of tobacco) and has a history of exposure to open log fires for cooking, has been suffering from COPD for the last 4 years. She has been taking inhaled betamethasone and tiotropium. Additionally, she had uncontrolled diabetes for a few months. She presented with fever, productive cough, shortness of breath and chest pain for 5 days. She required non-invasive ventilation support for type-2 respiratory failure. Chest X-ray and CT confirmed pneumonia, cavities and abscesses in both lungs. Repeated sputum and bronchoalveolar lavage confirmed coinfections with Pseudomonas aeruginosa and Aspergillus fumigatus, respectively. Along with supportive therapy, she was treated with tablet levofloxacin and injection amikacin for 6 weeks based on culture sensitivity reports, and capsule itraconazole for 6 months. She recovered completely to her baseline COPD and diabetes status. This case study confirms that coinfections can occur in COPD and diabetes, highlighting the need for clinicians to be vigilant for the possibility of such symbiotic coinfections.

Influenza-associated and COVID-19-associated pulmonary aspergillosis in critically ill patients.

Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are increasingly recognised as important complications in patients requiring intensive care for severe viral pneumonia. The diagnosis can typically be made in 10-20% of patients with severe influenza or COVID-19, but only when appropriate diagnostic tools are used. Bronchoalveolar lavage sampling for culture, galactomannan testing, and PCR forms the cornerstone of diagnosis, whereas visual examination of the tracheobronchial tract during bronchoscopy is required to detect invasive Aspergillus tracheobronchitis. Azoles are the first-choice antifungal drugs, with liposomal amphotericin B as an alternative in settings where azole resistance is prevalent. Despite antifungal therapy, IAPA and CAPA are associated with poor outcomes, with fatality rates often exceeding 50%. In this Review, we discuss the mechanistic and clinical aspects of IAPA and CAPA. Moreover, we identify crucial knowledge gaps and formulate directions for future research.

Chronic pulmonary aspergillosis incidence in newly detected pulmonary tuberculosis cases during follow-up.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) is known to complicate patients with post-tubercular lung disease. However, some evidence suggests that CPA might co-exist in patients with newly-diagnosed pulmonary tuberculosis (P.TB) at diagnosis and also develop during therapy. The objective of this study was to confirm the presence of CPA in newly diagnosed P.TB at baseline and at the end-of-TB-therapy. MATERIALS AND METHODS: This prospective longitudinal study included newly diagnosed P.TB patients, followed up at third month and end-of-TB-therapy with symptom assessment, anti-Aspergillus IgG antibody and imaging of chest for diagnosing CPA. RESULTS: We recruited 255 patients at baseline out of which 158 (62%) completed their follow-up. Anti-Aspergillus IgG was positive in 11.1% at baseline and 27.8% at end-of-TB-therapy. Overall, proven CPA was diagnosed in 7% at baseline and 14.5% at the end-of-TB-therapy. Around 6% patients had evidence of aspergilloma in CT chest at the end-of-TB-therapy. CONCLUSIONS: CPA can be present in newly diagnosed P.TB patients at diagnosis and also develop during anti-tubercular treatment. Patients with persistent symptoms or developing new symptoms during treatment for P.TB should be evaluated for CPA. Whether patients with concomitant P.TB and CPA, while receiving antitubercular therapy, need additional antifungal therapy, needs to be evaluated in future studies.

Combined medical-interventional approaches for the management of complex fungal balls: a case series as a viable alternative in non-surgical patients.

Intracavitary pulmonary aspergilloma is a persistent and life-threatening infection that carries a mortality rate of up to 15%. It occurs when Aspergillus species gain entry to an existing lung cavity. In the absence of definitive treatment, patients may succumb to severe complications such as massive hemoptysis, cachexia, or secondary infections. Aspergillomas often show limited response to antifungal medications, mainly due to insufficient drug concentrations within the cavities. Surgery is frequently the preferred treatment option, but it poses significant risks, and many individuals are ineligible due to underlying health issues. We present the most extensive non-surgical fungal ball cohort to date, managed using an innovative multimodal strategy that combines antifungal therapy before and after bronchoscopic debulking. This was a cross-sectional observational study. For those who cannot undergo surgery, our medical center has pioneered a multimodal approach to aspergilloma resection. This approach combines bronchoscopic endoscopy with antifungal therapy and has been applied successfully to more than 18 patients that are presented in this series. The median age of the cohort was 58 years (range: 32-73), with an equal sex distribution. The mean percent predicted FEV1 was 65.3%. The mean follow-up duration was 3.6 years (range: 0.5-10 years). The cohort receiving antifungals systematically prior to debridement showed a reduction of the pre-existing cavity (40.38 mm versus 34.02 mm, p = 0.021). Across the 18 patients during the follow-up period, 94% remained recurrence-free (defined by symptoms and radiology). Our study fills a critical knowledge gap regarding the significance of initiating antifungal treatment before bronchoscopic debulking and presents a viable approach in these cases for which there is a current unmet therapeutic need.

The use of both medical and interventional methods to treat difficult fungal masses: A collection of cases showing efficacy for patients who can't undergo surgeryIntracavitary pulmonary aspergilloma is a serious and potentially deadly infection with a death rate of up to 15%. It happens when certain types of fungi invade existing lung cavities. Without proper treatment, patients may experience severe complications like heavy bleeding from the lungs, weight loss, or other infections. Traditional antifungal medications often don't work well because they can't reach high enough concentrations in the cavities. Surgery is usually the best option, but it's risky and not possible for many due to other health problems. Our study introduces a new way to treat aspergilloma without surgery. We've treated a significant number of patients using a combination of antifungal drugs and a procedure called bronchoscopic debulking. This involves removing the fungal growth using a thin tube inserted through the airways. Our research involved observing 18 patients treated this way. They were mostly middle-aged, with equal numbers of men and women. Their lung function was moderately impaired, and we followed them for an average of 3.6 years. We found that giving antifungal drugs before the debulking procedure helped reduce the size of the cavities. After treatment, almost all patients remained free of symptoms and signs of recurrence. This study highlights the importance of starting antifungal therapy before bronchoscopic debulking and offers a promising option for patients who can't have surgery.

Use of nebulized liposomal amphotericin B and posaconazole as antifungal prophylaxis in patients with severe SARS-CoV2 infection in intensive care unit.

PURPOSE: COVID-19 associated pulmonary aspergillosis (CAPA) is common and linked with high fatality rates. To assess the impact on the incidence and outcome of CAPA of an antifungal prophylaxis (AFP) we compared two cohorts of COVID-19 patients admitted to intensive care units (ICU) in Brescia, Italy, from January to August 2021. METHODS: The study cohort included all mechanically ventilated patients observed between April 2021 and August 2021 with SARS-CoV-2-pneumonia, who received AFP with oral posaconazole (200 mg every 6 h) and nebulized liposomal amphotericin B (50 mg every 2 weeks) from ICU admission to 7 days after discharge or, if applicable, until tracheostomy removal. The control cohort included COVID-19 patients admitted to the same ICU between January and March 2021 who did not receive any AFP. Subjects with CAPA at ICU admission were excluded. RESULTS: We included 270 patients, of whom 64 (23.7%) received AFP. In patients in the study group, CAPA-related mortality was significantly reduced (29% vs. 48% p = 0.04), as well as the incidence of CAPA (3.1% vs 12.1%, p = 0.03). Patients who developed CAPA were older (mean of 70-y-old vs 63-y-old, p < 0.001). One subject discontinued posaconazole due to an adverse reaction. Among the 46 patients who received it, only one patient reached an effective plasma concentration of posaconazole. CONCLUSION: AFP was associated with reduced incidence and mortality from CAPA and was well tolerated in patients with severe COVID-19. Posaconazole concentrations below the efficacy threshold in almost all patients may be attributable to drug interactions and prompt further studies to define its clinical significance.

Pulmonary scedosporiosis in an intractable immunocompetent host: A case report and literature review.

Pulmonary scedosporiosis is a rare pulmonary infection that often presents with nonspecific symptoms and radiological findings. In this report, we present a case of localized pulmonary scedosporiosis in an immunocompetent patient and analyze a total of 25 immunocompetent patients with pulmonary scedosporiosis. Through this case and the literature, we highlight the importance of considering pulmonary scedosporiosis in patients with nonspecific clinical symptoms and radiological findings resembling aspergilloma. This case and the literature further emphasize the significance of surgical intervention. Regardless of the use of antifungal drugs, surgery should be conducted as soon as possible.

Aspergillus nodules: Natural history and the effect of antifungals.

BACKGROUND: Aspergillus nodules are classified as a subset of chronic pulmonary aspergillosis. The optimal management approach is not known as their natural evolution following biopsy, the rate of progression to chronic cavitary pulmonary aspergillosis (CCPA) and the effect of antifungal treatment have not been described. OBJECTIVES: To describe the clinical course of patients diagnosed with Aspergillus nodules and the effect of antifungal treatment. PATIENTS/METHODS: We present a series of 23 patients with histologically confirmed Aspergillus nodules and describe serial imaging, antifungal treatment and progression to other diagnoses. RESULTS: Thirteen patients were diagnosed after a CT-guided biopsy and 10 after surgical resection. Among those who had CT-guided biopsy, 8 did not receive antifungal treatment; the nodule was stable or smaller in all cases on subsequent CT scan after a mean of 15.5 months. However, one patient developed squamous cell carcinoma after 16 months and another developed CCPA after 7 months. Among the 5 patients who received antifungals for at least 4 weeks, the nodule was smaller in 1 and stable in 4. One patient developed CCPA 3 years after the biopsy. No patient who had a surgical resection subsequently had a CCPA diagnosis. CONCLUSION: Most Aspergillus nodules remained stable or improved following biopsy, irrespective of the effect of antifungals. However, CCPA can develop occasionally in patients with Aspergillus nodules and ongoing radiological follow-up may be warranted when the nodule is not resected.

Antifungal Resistance in Pulmonary Aspergillosis.

Aspergilli may cause various pulmonary diseases in humans, including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and acute invasive pulmonary aspergillosis (IPA). In addition, chronic colonization may occur in cystic fibrosis (CF). Aspergillus fumigatus represents the main pathogen, which may employ different morphotypes, for example, conidia, hyphal growth, and asexual sporulation, in the various Aspergillus diseases. These morphotypes determine the ease by which A. fumigatus can adapt to stress by antifungal drug exposure, usually resulting in one or more resistance mutations. Key factors that enable the emergence of resistance include genetic variation and selection. The ability to create genetic variation depends on the reproduction mode, including, sexual, parasexual, and asexual, and the population size. These reproduction cycles may take place in the host and/or in the environment, usually when specific conditions are present. Environmental resistance is commonly characterized by tandem repeat (TR)-mediated mutations, while in-host resistance selection results in single-resistance mutations. Reported cases from the literature indicate that environmental resistance mutations are almost exclusively present in patients with IA indicating that the risk for in-host resistance selection is very low. In aspergilloma, single-point mutations are the dominant resistance genotype, while in other chronic Aspergillus diseases, for example, ABPA, CPA, and CF, both TR-mediated and single-resistance mutations are reported. Insights into the pathogenesis of resistance selection in various Aspergillus diseases may help to improve diagnostic and therapeutic strategies.

Microbiological Diagnosis of Pulmonary Aspergillus Infections.

As microbiological tests play an important role in our diagnostic algorithms and clinical approach towards patients at-risk for pulmonary aspergillosis, a good knowledge of the diagnostic possibilities and especially their limitations is extremely important. In this review, we aim to reflect critically on the available microbiological diagnostic modalities for diagnosis of pulmonary aspergillosis and formulate some future prospects. Timely start of adequate antifungal treatment leads to a better patient outcome, but overuse of antifungals should be avoided. Current diagnostic possibilities are expanding, and are mainly driven by enzyme immunoassays and lateral flow device tests for the detection of Aspergillus antigens. Most of these tests are directed towards similar antigens, but new antibodies towards different targets are under development. For chronic forms of pulmonary aspergillosis, anti-Aspergillus IgG antibodies and precipitins remain the cornerstone. More studies on the possibilities and limitations of molecular testing including targeting resistance markers are ongoing. Also, metagenomic next-generation sequencing is expanding our future possibilities. It remains important to combine different test results and interpret them in the appropriate clinical context to improve performance. Test performances may differ according to the patient population and test results may be influenced by timing, the tested matrix, and prophylactic and empiric antifungal therapy. Despite the increasing armamentarium, a simple blood or urine test for the diagnosis of aspergillosis in all patient populations at-risk is still lacking. Research on diagnostic tools is broadening from a pathogen focus on biomarkers related to the patient and its immune system.