Metagenomics next-generation sequencing for diagnosis of invasive fungal diseases in patients with hematological diseases

To investigate the characteristics and associated factors of invasive fungal disease in patients with systemic lupus erythematosus from Southern China. A retrospective study was performed. Demographic and clinical characteristics, laboratory data, and radiographic manifestations were recorded. A total of 45 lupus patients with invasive fungal disease (incidence 1.1%) were included. Twenty-three cases (51.1%) were infected with mold and 22 cases (48.9%) with yeast. Aspergillus spp. (44.4%) and Cryptococcus spp. (33.3%) were common. Aspergillosis mainly occurred in the lung. Cryptococcosis developed in the lung (40.0%), meninges (46.7%) and bloodstream (13.3%). Compared with yeast infection, mold infection tended to develop in patients with active lupus nephritis (65.2% vs. 31.8%, P = 0.03) and the mortality rate was higher (20.0% vs. 0%, P = 0.001). Co-infection with bacteria, virus or superficial fungi occurred in 12 patients (26.7%). Multivariate logistic regression analysis indicated that lymphopenia (odds ratio 2.65, 95% confidential interval 1.14-6.20, P = 0.02) and an accumulated dose of glucocorticoid (odds ratio 1.58, 95% confidence interval 1.10-2.25, P = 0.01) was associated with invasive fungal disease in lupus patients. Mold infection tended to develop in patients with active lupus disease with high mortality. Co-infection is not rare. Lymphopenia and an accumulated dose of glucocorticoid are associated with invasive fungal disease in lupus patients.

Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study

This study aimed to assess whether genetic variants of dendritic cell-associated C-type lectine-1 (Dectin-1), Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) influence the susceptibility to pulmonary invasive fungal disease (IFD) in patients with acute myeloid leukemia (AML) from a Chinese Han population. Eight single nucleotide polymorphisms (SNPs) of Dectin-1 (rs16910526, rs3901533, and rs7309123), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) and MyD88 (rs4988453 and rs4988457) in the genomic DNA of 172 adult AML patients were genotyped. Pulmonary IFD was diagnosed as proven or probable according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus guidelines. SNPs that were significant in the univariate analysis were further analyzed using the multiple logistic regression analysis to determine their association with the occurrence of pulmonary IFD. The mRNA expression of Dectin-1 was detected according to the genotype by quantitative realtime PCR (qRT-PCR), and the correlation of this expression with the occurrence of pulmonary IFD in AML patients was analyzed. Two Dectin-1 intron SNPs (rs3901533 and rs7309123) were found to be significantly associated with the susceptibility to pulmonary IFD in AML patients in a Chinese Han population. Significant associations were noted between pulmonary IFD and Dectin-1 rs3901533 dominant model (G/T+G/G vs. T/T, OR: 2.158; 95% CI: 1.109-4.2, P=0.02), Dectin-1 rs3901533 G allele (OR: 2.201; 95% CI: 1.206-4.019, P=0.01), or Dectin-1 rs7309123 C allele (OR: 1.919; 95% CI: 1.047-3.518, P=0.03). There were no significant associations between pulmonary IFD and the remaining Dectin-1 SNPs (rs16910526), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) or MyD88 (rs4988453 and rs4988457). In conclusion, two Dectin-1 SNPs (rs3901533 and rs7309123) are associated with increased susceptibility to pulmonary IFD in AML patients in a Chinese Han population.

The burden of invasive fungal diseases (IFDs) in patients with complicated alcoholic hepatitis (CAH)-defined by ≥ 2 hepatic (ascites, jaundice, liver failure, encephalopathy) or extrahepatic (coagulopathy, shock, kidney or respiratory failure) dysfunctions within 30 days-remains poorly characterised. To assess the burden of IFDs in CAH and compare it with bacterial pneumonia (BP). We conducted a retrospective nationwide cohort study of adult CAH patients in France (2012-2021). The primary exposure were IFDs. The primary outcome was 3-month mortality or liver transplantation. Associations were assessed with adjusted odds ratios (aORs) in complete-case and propensity score-matched cohorts. A 6-week landmark analysis and time-dependent Cox models were used to evaluate time-varying effects. Among 11,434 CAH patients (median age 55 years; 72% male), 2.2% and 15% developed IFDs and BP, respectively. Three-month survival was 17.5% (95% CI: 13.0-23.0) in IFDs, 46.8% (44.3-49.3) in BP and 60.0% (59.4-61.4) in those without either (p < 0.001). IFDs occurred in 44.3% of patients with BP, and BP increased IFD risk (aOR 2.93, 95% CI: 2.23-3.84). In matched analyses, IFDs were associated with a fourfold increase in mortality (aOR 4.58, 95% CI: 3.02-7.20), while BP showed a lower association (aOR 1.23, 95% CI: 1.06-1.43). IFDs were strong time-dependent predictors of death. IFDs affected 1 in 50 CAH patients and carried a disproportionate mortality risk, compared with BP. These findings support the implementation of targeted screening and early antifungal strategies in CAH management, as for BP.

Background: Posaconazole is superior to fluconazole/itraconazole in preventing invasive fungal diseases (IFDs) in neutropenic patients. Whether the higher cost of posaconazole is offset by decreases in IFDs in a given institute requires cost-effective analysis encompassing the spectrum of IFDs and socioeconomic factors specific to that geographic area. Methods: This study performed a cost-effective analysis of posaconazole prophylaxis for IFDs in an Asian teaching hospital, employing decision modeling and data of IFDs and medication costs specific to the institute, in neutropenic patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Results: In the cost-effectiveness analysis, the higher cost of posaconazole was partially offset by a reduction in the cost of treating IFDs that were prevented, resulting in an incremental cost of 125,954 Hong Kong dollars/16,148 USD per IFD avoided. Over a lifetime horizon, assuming same case fatality rate of IFDs in both groups, use of posaconazole results in 0.07 discounted life years saved. This corresponds to an incremental cost of 116,023 HKD/14,875 USD per life year saved. This incremental cost per life year saved in posaconazole prophylaxis fulfilled the World Health Organization defined threshold for cost-effectiveness. Conclusion: Posaconazole prophylaxis was cost-effective in Hong Kong.

Objective To investigate the efficacy and safety of posaconazole in the prophylaxis or salvage treatment of invasive fungal disease (IFD) in patients with hematological diseases. Methods 25 patients with hematological diseases receiving posaconazole treatment from Feb 2014 to Feb 2015 were analyzed retrospectively. The patients'average age was 32.6 years old (16-64 years old). 18 patients received posaconazole for IFD prophylaxis, and 7 patients for IFD salvage treatment. Results 18 patients receiving posaconazole for IFD prophylaxis had no clinical manifestation of IFD (that is no case of breakthrough fungal infection) during treatment or in the 12 weeks after treatment, and the average prophylaxis period was 21 d (14-35 d). Among 7 patients receiving posaconazole for IFD salvage treatment, 6 patients were effective, including 4 cases cured and 2 cases effective. There were no obviously side effects of posaconazole in these patients. Conclusion Posaconazole has good clinical response for IFD in the hematologic diseases patients whether in prophylaxis or in salvage treatment. Key words: Mycoses; Posaconazole; Treatment outcome

To investigate the efficacy and clinical safety of posaconazoleon primary antifungal prophylaxis against invasive fungal disease (IFD) in patients with stem cell transplantation. At the start from preconditioning regimen, 45 patients without IFD were administered with posaconazoleon until neutrophils greater than 0.5×109/L, 35 patients treated with micafungin were enrolled in control group. The incidence, risk factors of IFD and side effects of medicines were evaluated. Of the total 80 patients, 13(16%) had IFD within 100 days after allo-HSCT. The overall survival was significantly different between patients with or without IFD by Kaplan-Meier survival curve analysis (P<0.05). Out of the 45 cases in posaconazoleon group, IFD occurred in 4 cases (9%). In contrast, the incidence of IFD in control group was 26%(9 out of 35) (P<0.05). The risk factors of IFD and side effects were not significantly different between 2 groups(P>0.05). The primary prevention efficancy of IFD by posaconazoleon after allo-HSCT is much better than that of micafungin with well tolerability and satisfactory efficacy.

Invasive fungal diseases (IFDs) are life-threatening events in patients with haematologic disorders, and the spectrum of the aetiological pathogens continues to expand. This study aimed to evaluate the clinical utility of a panfungal polymerase chain reaction (PCR) assay for the management of IFDs in such patients. We prospectively analysed 273 consecutive blood samples from 64 risk episodes in 51 patients with haematologic disorders at high risk for IFD who were treated at our hospital between April 2007 and October 2010. PCR-positive results were obtained in 18 of 64 risk episodes (35.3%). IFD was documented in 14 episodes (21.9%, 9 probable IFDs and 5 possible IFDs) according to the revised criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. PCR was positive in all of these 14 episodes, and in 4 of the 50 episodes with no IFD category. Sensitivity, specificity, positive predictive value, and negative predictive value of our assay were 100%, 92%, 78% and 100% respectively. A considerable number of fungi (44.4%) that are less common than Aspergillus and Candida species were positive by PCR. Molecular diagnoses of Cunninghamella species, Aspergillus ustus, Fusarium species, Scedosporium apiospermum, Rhodotorula species and Rhizopus species were beneficial in selecting suitable treatments. Our panfungal PCR approach allows for the highly sensitive and specific detection and identification of a wide spectrum of fungal pathogens, which provides indispensable information for managing IFDs, especially refractory or breakthrough IFDs during antifungal therapy in high-risk patients with haematologic disorders.

To explore the epidemiological profiles of invasive fungal disease (IFD) in hospitalized patients with hematological diseases during 2007-2012. A total of 419 IFD patients with hematological diseases from January 2007 to December 2012 were reviewed. All of them were analyzed with regards to diagnostic levels, infection sites and various related factors. (1) A total of 233 cases (55.61%) were preliminarily identified as IFD, 140 cases (33.41%) had a clinical diagnosis and 46 cases (10.98%) were confirmed cases of IFD. (2) Among 46 confirmed cases of IFD, there were agranulocytosis (n = 43) and aspergillosis infection (n = 36). (3) Respiratory tract was the most frequent infection site in all IFD patients (85.20%) . (4) And chemotherapy-induced agranulocytosis was a major reason for IFD patients with hematological diseases. The number of IFD patients without chemotherapy had a rising trend. (5) The age group of IFD was during 41-60 years old. (6) All of them stayed on antibiotic therapy at the diagnosis of IFD. The numbers of antibiotics were two(205 cases, 48.93%) and three(179 cases, 42.72%). (7) The peak incidence of IFD was recorded in January, July and December. And June was another lower peak. Agranulocytosis is the main reason for IFD patients with hematological disease. The data is important and valuable for the early diagnosis and therapy of IFD patients with hematological disease.

To evaluate the efficacy and safety of low-dose amphotericin B (AmB) in different antifungal strategies for treatment of invasive fungal disease(IFD) in patients with hematologic malignancies. Metheds: The clinical dada of the patients were collected and analyzed retrospectively and the levels of creatinine (Cr), urea nitrogen (BUN) and potassium (K+) before and after using low-dose AmB were compared and statistically analyzed. Among 97 cases, 2 cases were diagnosed as invasive fungal disease (IFD), 11 cases were diagnosed as clinical probable IFD, 15 cases were diagnosed as possible IFD, 69 cases were undefined IFD. The response rate of all patients treated with low-dose AmB was 69.4%, the response rate for targed therapy was 72.7%, the response rate for diagnosis-driven therapy was 63.6%, the response rate of empirical therapy was 75%, the efficacy of the combination with other antibiotics was 50%, 66.7% and 75%. According to all the patients received AmB, only 7 cases was detected with higher level of Cr (7.2) than normal and this level come back to normal with in 7 days after drug withdrew. Although the Cr level in serum after 1 day of drug withdrew was higher than that before administration of drug(64.86±3.00 vs 58.76±1.67 µmol/L) and was with statistical difference(P<0.05), but did not show significant difference in comparison with the level after drug withdrew 7 days (58.43±1.68 µmol/L,P>0.05). AmB injection is an effective and safe method in empirical therapy and diagnosis-driven antifungal therapy for neutropenic, febrile patients with hematological malignancies.

Efficacy and Safety of Micafungin As Salvage Treatment for Invasive Fungal Disease in Patients with Hematologic Malignancies

Background: Empirical antifungal therapy is effective in some patients with risk factors for invasive fungal disease (IFD) who do not qualify for the EORTC/MSG criteria for IFD, but who fail to respond to anti-bacterial and anti-viral therapy. Objective: This retrospective single-center study investigated the epidemiology of IFD and empirical antifungal therapy in patients with hematological malignancies. Methods: This study recruited 893 patients with hematologic malignancies who had failed to respond to anti-bacterial and anti-viral treatment and received antifungal therapy, but not for antifungal prophylaxis. Antifungal therapy regimens included amphotericin B, voriconazole, itraconazole and caspofungin. A total of 689 patients were diagnosed with proven, probable, or possible IFD, while 159 patients did not meet the EORTC/MSG criteria for IFD diagnosis but recovered with antifungal treatment, and 45 were excluded from having IFD. Effective treatment was defined as the disappearance or resolution of clinical symptoms of IFD. Results: Patients diagnosed with IFD underwent chemotherapy at a higher proportion, and had significantly higher neutrophil counts compared to those who did not qualify for the EORTC/MSG criteria for IFD but responded to antifungals. The mortality due to all causes within 3 months was significantly higher for patients diagnosed with proven IFD, compared with those who did not qualify for the EORTC/MSG criteria for IFD. There was no discontinuation reported due to adverse events of caspofungin. Conclusion: Empirical antifungal treatment could help save the lives of some patients with severe infections who are strongly suspected of having IFD.

Invasive fungal disease is associated with increased morbidity and mortality in hematologic malignancy patients and hematopoietic stem cell transplant recipients. Timely recognition and treatment of invasive fungal diseases in these patients are essential and decrease mortality. However, conventional definitive diagnostic methods are difficult and time consuming. While conventional microbiological and histopathological methods are still needed for a definitive diagnosis of invasive fungal disease, new noninvasive diagnostic methods including serologic and molecular biomarkers are now available. These new diagnostic methods facilitate an early diagnosis of invasive fungal disease and allow for utilization of a pre-emptive treatment approach, which may ultimately lead to improved treatment outcomes and reduced toxicity.

IntroductionThe incidence of invasive fungal diseases (IFDs) has risen in hematologic malignancy patients due to neutropenia. While posaconazole is recommended as the first-line antifungal prophylaxis in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and voriconazole is an alternative, there is currently no direct comparison data available to assess their relative effectiveness.MethodWe retrospectively reviewed eligible patient charts from January 2017 to February 2019 to identify breakthrough IFD rates, drug adverse event frequency, and drug acquisition cost in AML/MDS patients.ResultsForty-eight patients received 130 chemo cycles, with 50 (38%) cycles prescribed posaconazole and 80 (62%) prescribed voriconazole as primary IFD prophylaxis. The incidence rates of IFD in the posaconazole group were 8% (4 out of 50), of which two were probable and two were possible infections, while 6.26% (5 out of 80) of patients in the voriconazole group developed IFD, with four possible infections and one probable infection (p = 0.73). A higher percentage of patients in the voriconazole group discontinued prophylaxis due to adverse events, with six patients compared to two patients in the posaconazole group (p = 0.15). The drug acquisition cost of posaconazole is 5.62 times more expensive than voriconazole.ConclusionThe use of voriconazole instead of posaconazole for 130 chemo cycles would save $166,584.6. Posaconazole and voriconazole have comparable efficacy and safety in preventing IFD in AML and MDS patients receiving chemotherapy. However, posaconazole is more costly than voriconazole.

Several studies have suggested an association of mannose-binding lectin (MBL) deficiency with infections. In this study, we investigated the association between MBL deficiency and invasive fungal disease (IFD) in hematologic malignancy patients receiving myelosuppressive chemotherapy or hematopoietic stem cell transplant. MBL levels were quantified at the start of treatment in 152 patients who were followed for 6 months and scored as developing IFD or not. Forty-five patients (29.6%) developed IFD, of which 21 (46.7% of IFD cases and 13.8% of patients) were proven or probable IFD. Fifty-nine (38.8%) had MBL levels <1000 ng/mL. The rates of all IFD in patients with MBL levels below and above 1000 ng/mL were 33.9% and 26.9%, respectively (P=0.356). The rates of proven or probable IFD in patients with MBL levels below and above 1000 ng/mL were 11.9% and 15.1%, respectively (P=0.579). MBL levels <1000 ng/mL were not predictors of death (P=0.233). As expected, IFD was associated with death (P<0.0001). Our findings indicate that MBL levels <1000 ng/mL were not associated with an increased risk of developing IFD or overall survival.