Recent Advances in Diagnosing Chronic Pulmonary Aspergillosis

Purpose: The diagnosis of chronic pulmonary aspergillosis (CPA) is occasionally complicated due to poor sensitivity of mycological culture and colonization of Aspergillus species in the airway. Several diagnostic methods have been developed for the diagnosis of invasive pulmonary aspergillosis; however, their interpretation and significance are different in CPA. This study aimed to review the recent advances in diagnostic methods and their characteristics in the diagnosis of CPA.Recent findings: Radiological findings of lung, histopathology, and culture are the gold standard of CPA diagnosis. Serodiagnosis methods involving the use of galactomannan and β-D-glucan have low sensitivity and specificity. An Aspergillus-specific IgG antibody assay showed good performance and had better sensitivity and reproducibility than conventional precipitant antibody assays. Currently, it is the most reliable method for diagnosing CPA caused by Aspergillus fumigatus, but evidence on its effectiveness in diagnosing CPA caused by non-fumigatus Aspergillus is lacking. Newly developed lateral flow device Aspergillus and detection of volatile organic compounds in breath have potential, but evidence on its effectiveness in diagnosing CPA is lacking. The increasing prevalence of azole-resistant A. fumigatus strains has become a threat to public health. Some of the azole-resistant-related genes can be detected directly from clinical samples using a commercially available kit. However, its clinical efficacy for routine use remains unclear, since resistance-related genes greatly differ among regions and countries.Conclusion: Several issues surrounding the diagnosis of CPA remain unclear. Hence, further investigations and clinical studies are needed to improve the accuracy and efficiency of CPA diagnosis

Paradoxical response to disseminated non-tuberculosis mycobacteriosis treatment in a patient receiving tumor necrosis factor-α inhibitor: a case report

Background: Biological agents such as tumor necrosis factor-α inhibitors are known to cause mycobacterium infections. Here, we report a disseminated non-tuberculosis case caused by TNF-α inhibitor therapy and a probable paradoxical response to antimycobacterial therapy.Case presentation: A 68-year-old man with relapsing polychondritis was refractory to glucocorticoid therapy; adalimumab was therefore administered in combination with oral glucocorticoids. Treatment with 40 mg of adalimumab led to rapid improvement of his clinical manifestations. The administration of tacrolimus (1 mg) was started as the dosage of oral glucocorticoids was tapered. However, the patient developed an intermittent high fever and productive cough 15 months after starting adalimumab treatment. A chest computed tomography scan revealed new granular shadows and multiple nodules in both lung fields with mediastinal lymphadenopathy, and Mycobacterium intracellulare was isolated from 2 sputum samples; based on these findings, the patient was diagnosed with non-tuberculosis mycobacteriosis. Tacrolimus treatment was discontinued and oral clarithromycin (800 mg/day), rifampicin (450 mg/day), and ethambutol (750 mg/day) treatment was initiated. However, his condition continued to deteriorate despite 4 months of treatment; moreover, paravertebral and subcutaneous abscesses developed and increased the size of the mediastinal lymphadenopathy. Biopsy of the mediastinal lymphadenopathy and a subcutaneous abscess of the right posterior thigh indicated the presence of Mycobacterium avium complex (MAC), and the diagnosis of disseminated non-tuberculosis mycobacteriosis was confirmed. Despite 9 months of antimycobacterial therapy, the mediastinal lymphadenopathy and paravertebral and subcutaneous abscesses had enlarged and additional subcutaneous abscesses had developed, although microscopic examinations and cultures of sputum and subcutaneous abscess samples yielded negative results. We considered this a paradoxical reaction similar to other reports in tuberculosis patients who had discontinued biological agent treatments, and increased the dose of oral glucocorticoids. The patient\u27s symptoms gradually improved with this increased dose and his lymph nodes and abscesses began to decrease in size.Conclusions: Clinicians should consider the possibility of a paradoxical response when the clinical manifestations of non-tuberculosis mycobacteriosis worsen in spite of antimycobacterial therapy or after discontinuation of tumor necrosis factor-α inhibitors. However, additional evidence is needed to verify our findings and to determine the optimal management strategies for such cases

Comparison of Intra-Familial Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Oseltamivir Using an Influenza Transmission Model and a Health Insurance Claims Database

Background: Influenza affects approximately a billion people globally, including > 10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model.Methods: Using the JMDC Claims Database, we identified index case (IC) as the first family member diagnosed with influenza during the 2018–19 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model.Results: The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N = 84 672) and OTV (N = 62 004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th–97.5th percentiles, 1.68–1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs’ age category, virus type, and month of onset revealed similar trends favoring BXM.Conclusions: BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment

Efficacy of early administration of liposomal amphotericin B in patients with septic shock: A nationwide observational study

Introduction: Liposomal amphotericin B (L-AMB), a broad spectrum anti-fungicidal drug, is often administered to treat invasive fungal infections (IFIs). However, the most suitable time to initiate treatment in septic shock patients with IFI is unknown.Methods: Patients with septic shock treated with L-AMB were identified from the Japanese Diagnosis Procedure Combination national database and were stratified according to L-AMB treatment initiation either at septic shock onset (early L-AMB group) or after the onset (delayed L-AMB group) to determine their survival rates following septic shock onset and the shock cessation period.Results: We identified 141 patients administered L-AMB on the day of or after septic shock onset: 60 patients received early treatment, whereas 81 patients received delayed treatment. Survival rates after septic shock onset were higher in the early L-AMB group than in the delayed L-AMB group (4 weeks: 68.4% vs 57.9%, P = 0.197; 6 weeks: 62.2% vs 44.5%, P = 0.061; 12 weeks: 43.4% vs 35.0%, P = 0.168, respectively). The septic shock cessation period was shorter in the early L-AMB group than in the delayed L-AMB group (7.0 ± 7.0 days vs 16.5 ± 15.4 days, P < 0.001), with a significant difference confirmed after adjusting for confounding factors with propensity score matching (7.1 ± 7.2 days vs 16.7 ± 14.0 days, P = 0.001).Conclusion: Early L-AMB administration at septic shock onset may be associated with early shock cessation

The impact of muscle mass loss and deteriorating physical function on prognosis in patients receiving hemodialysis

Muscle mass loss and worsening physical function are crucial issues in patients receiving hemodialysis (HD). However, few studies have investigated the association between temporal changes in muscle mass and physical function in a large number of HD patients. We examined 286 patients receiving HD (males, 58%; age, 66.8 ± 13.0 years) at a single center, and calculated the percent changes in psoas muscle mass index (%PMI) using computed tomography over two screenings, once per year (July 2011–June 2013). Physical function was evaluated using the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) (range 0–4). The observation period was from July 2012 to June 2021. The median %PMI was -9.5%, and those with the lowest quartile of %PMI (< −20.5%) showed a significantly poor prognosis compared with other patients (p < 0.001). Multivariable logistic regression analysis revealed that these patients tended to have decreased physical function (ECOG-PS 2–4) [odds ratio (OR): 2.46, p < 0.001] and albumin levels (OR: 0.22, p = 0.007). Multiple-factor-adjusted Cox regression analyses showed that %PMI (hazard ratio: 0.99, p = 0.004) and each ECOG-PS stage (1–4 vs. 0) (p < 0.01) were associated with mortality. Augmenting physical activities in daily life and serum albumin levels should be considered to maintain muscle mass and improve the prognosis of patients receiving HD

Association between potassium supplementation and the occurrence of acute kidney injury in patients with hypokalemia administered liposomal amphotericin B: a nationwide observational study

Background: Hypokalemia and acute kidney injury (AKI) occur in patients administered liposomal amphotericin B (L-AMB), a wide-spectrum anti-fungicidal drug. However, the association between potassium supplementation and the occurrence of AKI in patients with hypokalemia who were administered L-AMB is not well understood.Methods: Using nationwide claims data and laboratory data, the occurrence of AKI during L-AMB treatment was retrospectively compared between patients with hypokalemia who were or were not supplemented with potassium and between those adequately or inadequately supplemented with potassium (serum potassium levels corrected to ≥3.5 mEq/L or remained < 3.5 mEq/L, respectively) before or after L-AMB treatment initiation.Results: We identified 118 patients who developed hypokalemia before L-AMB treatment initiation (43 received potassium supplementation [25 adequate and 18 inadequate supplementation] and 75 did not receive potassium supplementation), and 117 patients who developed hypokalemia after L-AMB initiation (79 received potassium supplementation [including 23 adequate and 15 inadequate supplementation] and 38 did not receive potassium supplementation). The occurrence of any stage of AKI was similar between patients with hypokalemia, regardless of potassium supplementation (i.e., before L-AMB treatment initiation [supplementation, 51%; non-supplementation, 45%; P = 0.570] or after L-AMB initiation [supplementation, 28%; non-supplementation, 32%; P = 0.671]). After adjusting for confounding factors, we found that the occurrence of any stage of AKI was not associated with potassium supplementation before L-AMB initiation (odds ratio [OR]: 1.291, 95% confidence interval [CI]: 0.584–2.852, P = 0.528) or after L-AMB initiation (OR: 0.954, 95% CI: 0.400–2.275, P = 0.915). The occurrence of any stage of AKI tended to decline in patients with hypokalemia who were adequately supplemented with potassium (44%) before, but not after, L-AMB initiation relative to that in patients inadequately supplemented with potassium (61%), however this result was not significant (P = 0.358).Conclusion: Potassium supplementation was not associated with any stage of AKI in patients with hypokalemia who were administered L-AMB

Association between the psoas muscle index and hospitalization for pneumonia in patients undergoing hemodialysis

Background: Although muscle mass loss and pneumonia are common and crucial issues in hemodialysis (HD) patients, few reports have focused on their association, which remains unclear. This study assessed the association between skeletal muscle mass and the incidence of pneumonia in HD patients using the psoas muscle index (PMI).Methods: This retrospective study included 330 patients on HD who were treated at a single center between July 2011 and June 2012. The observation period was between July 2011 and June 2021. Demographic, clinical, and HD data were collected, and the associations between PMI and hospitalization due to bacterial pneumonia were evaluated using Cox proportional hazards models adjusted for patients’ background data. Additionally, the correlation between patient characteristics and PMI was evaluated using multivariable linear regression.Results: Among 330 patients (mean age, 67.3 ± 13.3; 56.7% male; median dialysis vintage 58 months, (interquartile range [IQR] 23–124), 79 were hospitalized for pneumonia during the observation period (median observation period was 4.5 years [IQR 2.0–9.1]). The multivariable Cox proportional analysis, which was adjusted for age, sex, dialysis vintage, diabetes mellitus, and stroke history and considered death as a competing risk, indicated that decreased PMI/(standard deviation) was closely associated with the development of pneumonia (hazard ratio: 0.67, 95% confidence interval: 0.47–0.95, p = 0.03).Conclusions: Skeletal muscle mass was associated with the development of pneumonia in patients on HD and could be a useful marker for the risk of pneumonia

Clinical characteristics and risk factors of enterococcal infections in Nagasaki, Japan: a retrospective study

Background: Enterococcus spp. are particularly important etiological agents of nosocomial infections. However, the clinical characteristics of and risk factors for enterococcal infections in clinical settings are poorly understood. Methods: The sample included patients with Enterococcus spp. infections detected from clinical samples at Nagasaki University Hospital between 2010 and 2011 and patients with enterococcal colonization (control patients). In this retrospective study, the risk factors for enterococcal infections were analyzed by comparing infected and control patients via multivariate logistic regression. Results: A total of 182 infected (mean age, 64.6±18.2years; 114 men) and 358 control patients (patients with enterococcal colonization) (mean age, 61.6±22.4years; 183 men) were included. Enterococcal infections were classified as intraperitoneal (n=87), urinary tract (n=28), or bloodstream (n=20) infections. Cancer and hematological malignancies were the most common comorbidities in enterococcal infections. Carbapenem and vancomycin were administered to 43.8% and 57.9% of patients infected with Enterococcus faecalis and Enterococcus faecium, respectively. No vancomycin-resistant enterococci were isolated. Multivariate analysis identified abdominal surgery (odds ratio [OR], 2.233; 95% confidence interval [CI], 1.529-3.261; p?0.001), structural abnormalities of the urinary tract (OR, 2.086; 95% CI, 1.088-4.000; p=0.027), male sex (OR, 1.504; 95% CI, 1.032-2.190; p=0.033), and hypoalbuminemia (OR, 0.731; 95% CI, 0.555-0.963; p=0.026) as independent risk factors for enterococcal infections. Multivariate analysis showed abdominal surgery (OR, 2.263; 95% CI, 1.464-3.498; p?0.001), structural abnormalities of the urinary tract (OR, 2.634; 95% CI, 1.194-5.362; p=0.008), and hypoalbuminemia (OR, 0.668; 95% CI, 0.490-0.911; p=0.011) were independent risk factors for E. faecalis infection. Finally, immunosuppressive agent use (OR, 3.837; 95% CI, 1.397-10.541; p=0.009) and in situ device use (OR, 3.807; 95% CI, 1.180-12.276; p=0.025) were independent risk factors for E. faecium infection. Conclusions: These findings might inform early initiation of antimicrobial agents to improve clinical success

ERG3-encoding sterol C5,6-DESATURASE in Candida albicans Is required for virulence in an enterically infected invasive candidiasis mouse model

Gastrointestinal colonization by Candida species is considered the main source of candidemia. The ERG3 gene in Candida albicans encodes a sterol C5,6-desaturase, which is essential for ergosterol biosynthesis. Although ERG3 inactivation shows reduced virulence in mouse models of disseminated candidiasis, the role of ERG3 in intestinal infections is unknown. Here, we infected mice with the C. albicans strains CAE3DU3 and CAF2-1, containing mutant and wild-type ERG3, respectively, and studied gut infection and colonization by these strains. We found that the CAE3DU3 strain showed reduced colonization, pathogenesis, damage to gut mucosa, and chemokine production in the mouse model of invasive candidiasis. Additionally, mice inoculated with CAE3DU3 showed lower mortality than mice inoculated with CAF2-1 (p < 0.0001). Chemokines were less induced in the gut inoculated with CAE3DU3 than in the gut inoculated with CAF2-1. Histopathologically, ]although the wild-type gene was associated with a higher pathogenicity and invasion of the gut mucosa and liver tissues causing remarkable tissue necrosis, the erg3/erg3 mutant was associated with a higher accumulation of cells and lower damage to surrounding tissues than wild-type ERG3. These results establish that the ergosterol biosynthetic pathway may be associated with C. albicans gut colonization and subsequent dissemination

Autophagy-Inducing Factor Atg1 Is Required for Virulence in the Pathogenic Fungus Candida glabrata

Candida glabrata is one of the leading causes of candidiasis and serious invasive infections in hosts with weakened immune systems. C. glabrata is a haploid budding yeast that resides in healthy hosts. Little is known about the mechanisms of C. glabrata virulence. Autophagy is a \u27self-eating\u27 process developed in eukaryotes to recycle molecules for adaptation to various environments. Autophagy is speculated to play a role in pathogen virulence by supplying sources of essential proteins for survival in severe host environments. Here, we investigated the effects of defective autophagy on C. glabrata virulence. Autophagy was induced by nitrogen starvation and hydrogen peroxide (H2O2) in C. glabrata.A mutant strain lacking CgAtg1, an autophagy-inducing factor, was generated and confirmed to be deficient for autophagy. The Cgatg1Δ strain was sensitive to nitrogen starvation and H2O2, died rapidly in water without any nutrients, and showed high intracellular ROS levels compared with the wild-type strain and the CgATG1-reconstituted strain in vitro. Upon infecting mouse peritoneal macrophages, the Cgatg1Δ strain showed higher mortality from phagocytosis by macrophages. Finally, in vivo experiments were performed using two mouse models of disseminated candidiasis and intra-abdominal candidiasis. The Cgatg1Δ strain showed significantly decreased CFUs in the organs of the two mouse models. These results suggest that autophagy contributes to C. glabrata virulence by conferring resistance to unstable nutrient environments and immune defense of hosts, and that Atg1 is a novel fitness factor in Candida species