A lesson from fatal invasive fungal infections after CAR-T cell therapy: a case report and literature review.

CD19 chimeric antigen receptor T (CAR-T) cell therapy represents an effective approach to treating patients with relapsed or refractory B-cell hematologic malignancies. Nevertheless, owing to the immunosuppressive effects of this regimen, patients undergoing CD19 CAR-T cell therapy may face an elevated risk of invasive fungal infections, which involve fungi penetrating the host's tissues or bloodstream, leading to life-threating infectious diseases. Herein, we present the case of a 17-year-old male diagnosed with acute lymphoblastic leukemia, who subsequently experienced a fatal invasive fungal infection following administration of CAR-T cell therapy. Furthermore, we delve into the identification of risk factors, implementation of preventive measures and exploration of therapeutic interventions for invasive fungal infections after CAR-T cell therapy.

A 17-year-old male was diagnosed with acute lymphoblastic leukemia and experienced disease relapse after undergoing multiple chemotherapy treatments. Subsequently, he participated in a clinical trial of CAR-T cell therapy at our institution. Due to a possible lung fungal infection, he was given oral antifungal medicine. Throughout the treatment period, he developed recurrent fever. After receiving immunosuppressive agents, he developed gangrene at the sinuses and was diagnosed with invasive fungal sinusitis. Although antifungal medication was adjusted, it failed to fully eradicate the infection, leading to the patient's recurrent shocks associated with the fungal infection. These findings underscore the importance for physicians to be vigilant regarding potential fungal infections when administering CAR-T cell therapy, particularly in patients with preexisting fungal infections prior to treatment. Likewise, caution should be exercised in the use of immunosuppressive agents, given their potential to increase the risk of fungal infections, among other complications. Early and timely surgical intervention in the presence of invasive fungal infections may be more effective than monotherapy in some patients with invasive fungal infections.

A systematic review and disability-adjusted life years of Scedosporium/Lomentospora infection in patients after near-drowning.

Scedosporium/Lomentospora species exist as saprophytic moulds that can potentially lead to serious infections in patients who have experienced near-drowning incidents. Scedosporium species are distributed across different regions of the world while Lomentospora prolificans has quite a restricted geographic distribution. We aimed to systematically review scedosporiosis cases after near-drowning, their clinical manifestations, underlying diseases, treatments, outcomes and its impact through disability-adjusted life years (DALYs). Five available sources were searched from 1 January 2007, to 20 April 2022. Thirty-eight studies, including 41 patients, were evaluated. Mean age was 33.6 ± 18.6 years (range 1-68), and 28 were male (68.3%). Central nervous system (CNS) dissemination predominated (36/41; 87.8%), presenting mainly as multiple brain abscesses (26/41; 63.4%), followed by lung involvement (22/41; 56.4%). Scedosporium apiospermum species complex was the most causative agent (38/41; 92.7%). Overall mortality was 51.2%. Half of the patients (18/37) were cured after receiving proper treatment, and in most cases, voriconazole alone or in combination with surgery or other antifungals caused survival. The mean survival time was 123 ± 27 days. Mean DALYs in 1980-2022 were 46.110 ± 3.318 (39.607-52.612). Time to diagnosis was estimated to be 120 days, and there was no association between time to diagnosis and outcome. Voriconazole is a potentially effective therapy, and combination of surgery and antifungal treatment may lead to more favourable outcome. Advances in early diagnosis and appropriate antifungal therapy may have contributed to reducing its mortality.

A diagnostic algorithm for early diagnosis and management of acute invasive fungal sinusitis.

PURPOSE: To define different risk groups of patients suspected of having acute invasive fungal sinusitis (AIFS) and develop a goal-directed diagnostic approach. MATERIALS AND METHODS: Forty patients with suspected AIFS biopsied from 2010 to 2020 were included in this study. Patients diagnosed with chronic invasive fungal sinusitis or without biopsy results were excluded. A recursive partitioning analysis (RPA) model was performed to define patient cohorts with the highest risk of having a positive biopsy for AIFS. RESULTS: There were a total of 26 patients with biopsy-proven AIFS. Patient characteristics significantly associated with an increased likelihood of a positive biopsy for AIFS on bivariate analysis included facial pain (p = 0.047), platelet count <50,000 cells/mm3 (p = 0.028), and abnormal CT findings, most commonly, bilateral sinus opacification (p = 0.003). The RPA model identified three risk factors for predicting a patient's probability of having a positive biopsy for AIFS, resulting in four-terminal nodes. In the twenty-six patients who had biopsy-proven AIFS, the post-operative 30-day all-cause mortality was 50 % (13/26) and overall mortality was 88.5 % (23/26). Predictors of 30-day all-cause mortality included prolonged interval between biopsy and operative start time (p = 0.042) and earlier initiation of antifungals prior to the operative start time (p = 0.042). CONCLUSION: Our findings indicate that patients with a fever of unknown origin, low platelet count, and/or ANC are at an increased risk of being diagnosed with biopsy-proven AIFS. Using these risk factors, we propose a diagnostic approach that may expedite the treatment of patients with AIFS; however, future prospective studies are needed for validation.

[Consensus on diagnosis and treatment of invasive fungal infection in patients with severe liver disease].

The prognosis of severe liver disease combined with invasive fungal infection (IFI) is poor, and the clinical manifestations are often atypical. Moreover, most of the antifungal drugs are metabolized in the liver, with severe toxicities and side effects, making clinical diagnosis and treatment difficult. The Professional Committee for Hepatology, the Chinese Research Hospital Association and the Hepatology Branch of China Medical Association organized relevant experts to formulate an expert consensus based on the characteristics of patients with severe liver disease combined with IFI, in order to provide reference for medical personnel in making decisions on the diagnosis and treatment.

Manipulating NK cellular therapy from cancer to invasive fungal infection: promises and challenges.

The ideal strategy to fight an infection involves both (i) weakening the invading pathogen through conventional antimicrobial therapy, and (ii) strengthening defense through the augmentation of host immunity. This is even more pertinent in the context of invasive fungal infections whereby the majority of patients have altered immunity and are unable to mount an appropriate host response against the pathogen. Natural killer (NK) cells fit the requirement of an efficient, innate executioner of both tumour cells and pathogens - their unique, targeted cell killing mechanism, combined with other arms of the immune system, make them potent effectors. These characteristics, together with their ready availability (given the various sources of extrinsic NK cells available for harvesting), make NK cells an attractive choice as adoptive cellular therapy against fungi in invasive infections. Improved techniques in ex vivo NK cell activation with expansion, and more importantly, recent advances in genetic engineering including state-of-the-art chimeric antigen receptor platform development, have presented an opportune moment to harness this novel therapeutic as a key component of a multipronged strategy against invasive fungal infections.

Consensus guidelines for the diagnosis and management of invasive fungal disease due to moulds other than Aspergillus in the haematology/oncology setting, 2021.

Invasive fungal disease (IFD) due to moulds other than Aspergillus is a significant cause of mortality in patients with malignancies or post haemopoietic stem cell transplantation. The current guidelines focus on the diagnosis and management of the common non-Aspergillus moulds (NAM), such as Mucorales, Scedosporium species (spp.), Lomentospora prolificans and Fusarium spp. Rare but emerging NAM including Paecilomyces variotii, Purpureocillium lilacinum and Scopulariopsis spp. are also reviewed. Culture and histological examination of tissue biopsy specimens remain the mainstay of diagnosis, but molecular methods are increasingly being used. As NAM frequently disseminate, blood cultures and skin examination with biopsy of any suspicious lesions are critically important. Treatment requires a multidisciplinary approach with surgical debridement as a central component. Other management strategies include control of the underlying disease/predisposing factors, augmentation of the host response and the reduction of immunosuppression. Carefully selected antifungal therapy, guided by susceptibility testing, is critical to cure. We also outline novel antifungal agents still in clinical trial which offer substantial potential for improved outcomes in the future. Paediatric recommendations follow those of adults. Ongoing epidemiological research, improvement in diagnostics and the development of new antifungal agents will continue to improve the poor outcomes that have been traditionally associated with IFD due to NAM.

Invasive Fungal Infections in Immunocompromised Children: Novel Insight Following a National Study.

OBJECTIVE: To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT). STUDY DESIGN: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units. RESULTS: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10-4) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents. CONCLUSIONS: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children.

Invasive Fungal Sinusitis in Post COVID-19 Patients: A New Clinical Entity.

OBJECTIVES: Occurrence of invasive fungal respiratory superinfections in patients with COVID-19 has gained increasing attention in the latest studies. Yet, description of acute invasive fungal sinusitis with its management in those patients is still scarce. This study aims to describe this recently increasing clinical entity in relation to COVID-19 patients. STUDY DESIGN: Longitudinal prospective study. METHODS: Prospective longitudinal study included patients diagnosed with acute invasive fungal rhinosinusitis after a recent COVID-19 infection. Antifungal agents given included amphotericin B, voriconazole, and/or posaconazole. Surgical treatment was restricted to patients with PCR negative results for COVID-19. Endoscopic, open, and combined approaches were utilized to eradicate infection. Follow-up for survived patients was maintained regularly for the first postoperative month. RESULTS: A total of 36 patients with a mean age of 52.92 ± 11.30 years old were included. Most common associated disease was diabetes mellitus (27.8%). Mycological analysis revealed infection with Mucor and Aspergillus species in 77.8% and 30.6% of patients, respectively. Sino-nasal, orbital, cerebral, and palatine involvement was found in 100%, 80.6%, 27.8%, and 33.3% of patients, respectively. The most common reported symptoms and signs are facial pain (75%), facial numbness (66.7%), ophthalmoplegia, and visual loss (63.9%). All patients were treated simultaneously by surgical debridement with antifungal medications except for two patients with PCR-positive swab for COVID-19. These two patients received antifungal therapy alone. Overall survival rate was 63.89% (23/36). CONCLUSION: Clinical suspicion of acute invasive fungal sinusitis among COVID-19 patients and early management with antifungal therapy and surgical debridement is essential for better outcomes and higher survival. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2652-2658, 2021.

[Invasive fungal infections in ICU patients - What's New?] / Invasive Pilzinfektionen bei Intensivpatienten ­ Was gibt es Neues?

Invasive fungal infections are gaining increasing importance in intensive care medicine. The aim of this article is to present an update on recent developments in the field of invasive fungal infection in critically ill patients. Particular emphasis is placed on the recently described invasive mold infections in patients with acute respiratory distress syndrome due to influenza or COVID-19. Detecting high-risk patients and the optimal diagnostic and therapeutic strategies play a decisive role to improve outcome.

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy - a case report.

BACKGROUND: Prolonged myelosuppression following CD19-directed CAR T-cell transfusion represents an important, yet underreported, adverse event. The resulting neutropenia and multifactorial immunosuppression can facilitate severe infectious complications. CASE PRESENTATION: We describe the clinical course of a 59-year-old patient with relapsed/refractory DLBCL who received Axicabtagene-Ciloleucel (Axi-cel). The patient developed ASTCT grade I CRS and grade IV ICANS, necessitating admission to the neurological ICU and prolonged application of high-dose corticosteroids and other immunosuppressive agents. Importantly, neutropenia was profound (ANC < 100/µl), G-CSF-refractory, and prolonged, lasting more than 50 days. The patient developed severe septic shock 3 weeks after CAR transfusion while receiving anti-fungal prophylaxis with micafungin. His clinical status stabilized with broad anti-infective treatment and intensive supportive measures. An autologous stem cell backup was employed on day 46 to support hematopoietic recovery. Although the counts of the patient eventually started to recover, he developed an invasive pulmonary aspergillosis, which ultimately lead to respiratory failure and death. Postmortem examination revealed signs of Candida glabrata pancolitis. CONCLUSIONS: This case highlights the increased risk for fatal infectious complications in patients who present with profound and prolonged cytopenia after CAR T-cell therapy. We describe a rare case of C. glabrata pancolitis associated with multifactorial immunosuppression. Although our patient succumbed to a fatal fungal infection, autologous stem cell boost was able to spur hematopoiesis and may represent an important therapeutic strategy for DLBCL patients with CAR T-cell associated bone marrow aplasia who have underwent prior stem cell harvest.

Chronic Granulomatous Invasive Fungal Sinusitis: A Case Series and Literature Review.

Chronic granulomatous invasive fungal sinusitis (CGIFS) is a peculiar disease of the paranasal sinuses due to its rarity, patient subset, and disease course. We describe 7 cases of histopathologically confirmed CGIFS with different treatment plans and varying outcomes. Of particular note was that one of these patients developed allergic fungal rhinosinusitis after complete resolution of his primary invasive disease, a finding that has never been reported in the literature. Another patient had an atypical fungal species (Aspergillus nidulans) on fungal stain and culture, while one immunodeficient patient had a large intracerebral disease component and died after 2 months of treatment. We also present a review of the pertinent literature investigating this rare disease.

Opportunistic Invasive Fungal Infections Mimicking Progression of Non-Small-Cell Lung Cancer.

BACKGROUND: Many studies have shown that invasive pulmonary aspergillosis, cryptococcosis, and mucormycosis can mimic radiographic and clinical features of primary lung cancer. However, more research surveying the incidence and outcomes of these fungal infections among patients with a history of lung cancer is needed. The aim of this study was to describe the occurrence and clinical outcomes of opportunistic invasive fungal infections that can mimic tumors in non-small-cell lung cancer patients. PATIENTS AND METHODS: Patients seen at Stanford University Medical Center from January 1, 2007, to May 1, 2020, with pulmonary aspergillosis, cryptococcosis, or mucormycosis after non-small-cell lung cancer (NSCLC) diagnosis were reviewed. The European Organization for Research and Treatment of Cancer National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria was used to classify patients with evidence of proven or probable invasive fungal infection within our cohort. RESULTS: A total of 12 patients with proven or probable invasive mold infection (including 8 cases of aspergillosis) and 1 patient with proven cryptococcosis were identified, without any cases of mucormycosis. Of this cohort, 6 patients (46%) showed radiographic findings that were found to be most consistent with lung cancer by radiologists. Eight cases (62%) were suspected of cancer recurrence or progression by the treatment team on the basis of additional considerations of medical history and clinical symptoms. Most patients had active NSCLC or had a history of recurrence without active NSCLC at the time of fungal discovery (11 patients; 85%). Most patients died without full recovery (7 patients; 54%). CONCLUSIONS: Invasive pulmonary aspergillosis and cryptococcosis can often be mistaken as cancer recurrence or progression in patients with a history of NSCLC because of mimicking radiographic and clinical characteristics.

Evaluation of knowledge and awareness of invasive fungal infections amongst resident doctors in Nigeria.

INTRODUCTION: it has been estimated that about 11.8% of the Nigerians suffer serious fungal infections annually. A high index of suspicion with early diagnosis and institution of appropriate therapy significantly impacts on the morbidity and mortality of invasive fungal infections (IFIs). METHODS: we conducted a cross-sectional multicentre survey across 7 tertiary hospitals in 5 geopolitical zones of Nigeria between June 2013 and March 2015. Knowledge, awareness and practice of Nigerian resident doctors about the diagnosis and management of invasive fungal infections were evaluated using a semi-structured, self-administered questionnaire. Assessment was categorized as poor, fair and good. RESULTS: 834(79.7%) of the 1046 participants had some knowledge of IFIs, 338(32.3%) from undergraduate medical training and 191(18.3%) during post-graduate (specialty) residency training. Number of years spent in clinical practice was positively related to knowledge of management of IFIs, which was statistically significant (p < 0.001). Only 2 (0.002%) out of the 1046 respondents had a good level of awareness of IFIs. Only 4(0.4%) of respondents had seen > 10 cases of IFIs; while 10(1%) had seen between 5-10 cases, 180(17.2%) less than 5 cases and the rest had never seen or managed any cases of IFIs. There were statistically significant differences in knowledge about IFIs among the various cadres of doctors (p < 0.001) as level of knowledge increased with rank/seniority. CONCLUSION: knowledge gaps exist that could militate against optimal management of IFIs in Nigeria. Targeted continuing medical education (CME) programmes and a revision of the postgraduate medical education curriculum is recommended.

Latest Thoughts on Treating Pediatric Mucormycosis.

Mucormycosis is one of the most complicated to diagnose and treat invasive fungal diseases. Diagnostic techniques have not significantly advanced in years, and recent international consensus treatment guidelines offer some insight into the current best approaches to treating this deadly invasive mold.

Safety Evaluation of an Alpha-Emitter Bismuth-213 Labeled Antibody to (1→3)-ß-Glucan in Healthy Dogs as a Prelude for a Trial in Companion Dogs with Invasive Fungal Infections.

Background: With the limited options available for therapy to treat invasive fungal infections (IFI), radioimmunotherapy (RIT) can potentially offer an effective alternative treatment. Microorganism-specific monoclonal antibodies have shown promising results in the experimental treatment of fungal, bacterial, and viral infections, including our recent and encouraging results from treating mice infected with Blastomyces dermatitidis with 213Bi-labeled antibody 400-2 to (1→3)-ß-glucan. In this work, we performed a safety study of 213Bi-400-2 antibody in healthy dogs as a prelude for a clinical trial in companion dogs with acquired invasive fungal infections and later on in human patients with IFI. Methods: Three female beagle dogs (≈6.1 kg body weight) were treated intravenously with 155.3, 142.5, or 133.2 MBq of 213Bi-400-2 given as three subfractions over an 8 h period. RBC, WBC, platelet, and blood serum biochemistry parameters were measured periodically for 6 months post injection. Results: No significant acute or long-term side effects were observed after RIT injections; only a few parameters were mildly and transiently outside reference change value limits, and a transient atypical morphology was observed in the circulating lymphocyte population of two dogs. Conclusions: These results demonstrate the safety of systemic 213Bi-400-2 administration in dogs and provide encouragement to pursue evaluation of RIT of IFI in companion dogs.

Risk and impact of invasive fungal infections in patients with multiple myeloma.

Infection is associated with great morbidity and mortality in patients with multiple myeloma (MM), but evidence for invasive fungal infections (IFIs) is lacking. We aimed to investigate risk factors for IFI in MM patients and to determine its impact on patients' survival. We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 2002 and October 2018. MM was diagnosed according to the International Myeloma Working Group criteria. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. All risk factors of IFI in MM patients were estimated using Cox regression models in the univariate and multivariate analyses. Of the 623 patients recruited, 22 (3.5%) were diagnosed with proven or probable IFI. Light chain disease (adjusted hazard ratio [HR] 6.74, 95% confidence interval [CI] 2.10-21.66), hemoglobin less than 8 g/dl (adjusted HR 3.34, 95% CI 1.32-8.42), serum albumin < 3.5 g/dl (adjusted HR 3.24, 95% CI 1.09-9.68), and having received allogeneic stem cell transplantation (allo-SCT) (adjusted HR 5.98, 95% CI 1.62-22.03) were significantly associated with IFI in the multivariate analysis. Contracting IFI was in turn associated with early mortality (adjusted HR 11.60, 95% CI 1.26-106.74). Light chain disease, anemia, hypoalbuminemia, and receiving allo-SCT were independent predictors of IFI in MM patients. The early mortality risk is much higher in those encountering IFI. Physicians must be aware of the rare but potentially lethal infections.

Initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children, adolescents, and young adults receiving delayed-release tablet and intravenous posaconazole.

Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal diseases. There are limited data on the optimal dosing, safety, and efficacy of the DRT and IV formulations in immunocompromised pediatric and adolescent patients. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Plasma concentrations ≥.7 µg/mL were considered therapeutic for prophylaxis and ≥1.0 µg/mL for treatment. Fifty-four patients (median age of 16 years) received DRT or IV formulations of posaconazole. Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL) (Figure 1). The median daily dose among patients <13 years of age who achieved the targeted initial concentrations was 7.3 mg/kg/day for the DRT formulation and 9.8 mg/kg/day for the IV formulation. The median daily dose among patients ≥13 years of age who achieved the targeted initial concentrations was 4.9 mg/kg/day for the DRT formulation and 5.6 mg/kg/day for the IV formulation. Thirty-six patients (67%) developed transaminitis, mostly grade 1. Our observations show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients <13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. [Figure: see text].

Saprochaete capitata aortitis in an immunocomopetent patient after myocardial revascularization.

Saprochaete species infection is a rare fungal disease reported so far only in immunocompromised patients. We describe the first case of aortitis caused by Saprochaete capitata, presenting as ascending aorta aneurysm, with secondary endophthalmitis in an immunocompetent patient. Infection by Saprochaete capitata is potentially fatal, with a mortality ranging from 50% to 90% of cases. In the present case aortic aneurysm caused by Saprochaete capitata aortitis was successfully treated by the combination of accurate diagnosis with surgical and specific antifungal therapy.