The management and outcome of cryptococcosis in patients with different immune statuses and treatment protocols: A multicenter real-world study in Jiangsu Province - China.

OBJECTIVE: The incidence of cryptococcosis is increasing in non-immunocompromised patients. However, the evidence on proper management is inadequate in this population. We conducted this multi-center real-world study in pulmonary cryptococcosis patients with different immune statuses, so as to provide practical evidence for optimized clinical management of cryptococcosis, especially for mild-to-moderate immunodeficient diseases patients. METHODS: This is a prospective observational study. The clinical data of patients with proven cryptococcosis were collected and analyzed from 7 tertiary teaching hospitals in Jiangsu Province, China from January, 2013 to December, 2018. Proven cases include pulmonary cryptococcosis, cryptococcal meningitis, cryptococcemia and cutaneous cryptococcosis. Patients were followed up over 24 months. According to their immune status, patients with cryptococcosis were divided into three groups, namely immunocompetent group (IC), mild-to-moderate immunodeficient diseases group (MID), severe immunodeficient diseases group (SID). Meanwhile, pulmonary crypotococcosis (PC) and extrapulmonary crypotococcosis (EPC) were also classified and analyzed. RESULTS: 255 proven cases of cryptococcosis were enrolled. Finally, 220 cases completed the follow-up. 143 proven cases (65.0%) were immunocompetent (IC), 41 cases (18.6%) were MID, and 36 cases (16.4%) were SID. 174 cases (79.1%) were PC and 46 cases (20.9%) were EPC. The mortality was significantly higher in SID and MID patients [47.2% (SID) vs. 12.2% (MID) vs. 0.0% (IC), p<0.001]. The mortality was also significantly higher in EPC patients [45.7% vs. 0.6% (PC), p<0.001]. Patients with alternative initial antifungal treatment had higher mortality than patients with guideline recommended initial treatment [23.1% vs. 9.5%, p=0.041]. In MID group, the mortality of receiving alternative initial antifungal treatment was significantly higher than recommended initial treatment [2/3 vs. 3/34(8.8%), p=0.043]. In pulmonary cryptococcosis patients with MID, the mortality was very similar to IC group [0.0% vs. 0.0% (IC)], lower than SID group [0.0% vs. 11.1% (SID), p=0.555]. However, in extrapulmonary cryptococcosis patients with MID, the mortality was significantly higher than that in IC [62.5% vs. 0.0% (IC)], and similar to SID patients [62.5% vs. 59.3% (SID)]. CONCLUSION: The immune status exert a significant influence on the management and prognosis of cryptococcosis patients. The mortality of cryptococcosis patients with MID is higher than that of immunocompetent patients. For MID patients with pure pulmonary cryptococcosis, it is acceptable to take the treatment recommended as IC patients. For the MID patients with extrapulmonary cryptococcosis, the mortality is high and the initial treatment should follow the regimen for SID patients. Following the recommended treatment regimen in the IDSA guideline can reduce mortality in patients with cryptococcosis. Starting on alternative initial antifungal treatment may bring worse outcomes.

The clinical value of Aspergillus-specific IgG antibody test in the diagnosis of nonneutropenic invasive pulmonary aspergillosis.

OBJECTIVES: Aspergillus-specific IgG antibody (Asp IgG) has been successfully applied in the diagnosis of chronic pulmonary aspergillosis. We explored its value in nonneutropenic invasive pulmonary aspergillosis (IPA) by a multicenter, prospective, and controlled study. METHODS: We enrolled 372 clinically suspected nonneutropenic patients with IPA from February 2015 to August 2022. After excluding 4 cases with Aspergillus colonization, the remaining 368 cases were finally confirmed as patients with IPA (n = 99), or non-IPA patients (n = 269) consisting of community-acquired pneumonia (n = 206), tuberculosis (n = 22), nontuberculous mycobacteria (n = 5), lung abscess (n = 6), or noninfectious diseases (n = 30). Asp IgG in plasma samples was tested by enzyme-linked immunosorbent assay. RESULTS: At cut-off value of ≥80 AU/mL, Asp IgG had much higher sensitivity (59.6% vs. 19.2%, p < 0.0001), but lower specificity (77.0% vs. 96.3%, p < 0.0001) than serum galactomannan (GM) (cut-off value of ≥1.0), and similar sensitivity (59.6% vs. 55.6%, p = 0.611) but lower specificity (77.0% vs. 91.2%, p = 0.001) than bronchoalveolar lavage fluid (BALF) GM (cut-off value of ≥1.0), respectively. Combination diagnosis of either positive for Asp IgG or BALF GM had higher sensitivity (81.0% vs. 55.6%, p = 0.002), but lower specificity (75.2% vs. 91.2%, p = 0.001) than BALF GM alone. The receiver operating characteristic curve showed that Asp IgG had an optimal diagnostic value when the cut-off value was 56.6 AU/ml, and the sensitivity and specificity were 77.8% and 63.9%, respectively. DISCUSSIONS: The diagnostic value of Asp IgG for IPA is superior to serum GM, and a little inferior to BALF GM in nonneutropenic patients with IPA. Considering the convenience of taking blood samples, it is a good screening and diagnostic method for nonneutropenic patients with IPA, especially for those who cannot bear invasive procedures.

Relationship Between Gender and 1-Year Mortality in ANCA-Associated Vasculitis Patients: A Single-Center Retrospective Analysis and Meta-Analysis.

Objective: The relationship between gender and short-term prognosis of patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is unclear, hence single-center retrospective analysis and meta-analysis were conducted to determine the relationship. Methods: Initially treated patients with AAV were retrospectively enrolled. Data of clinical manifestation, laboratory indicators, Birmingham vasculitis activity score (BVAS), therapeutic treatments, and the patients' situations within 1 year were recorded. First, we compared the basic characteristics between male and female patients. Second, the risk factors associated with a 1-year mortality rate of patients with AAV were evaluated. Finally, a meta-analysis was performed to explore the effect of gender on 1-year mortality in patients with AAV. Results: The study involved 84 patients with AAV, including 33 female and 51 male participants. In total, 14 people died (12 males and 2 females) and 70 survived in the 1st year. Statistical differences were noted in the age of onset, the course of the disease, WBC, HB, N, ESR, CRP, BUN, ALT and ALB, BVAS, and 1-year mortality rate between male and female participants. In male patients, elevated Scr, NLR, PLT, and RDW-CV were associated with poor AAV (P < 0.05) prognosis. The meta-analysis verified that male gender was an independent risk factor for the 1-year mortality of patients with AAV(OR = 1.54). Conclusion: Significant sex-specific differences were found in patients with AAV. Male patients contributed to 1.54-fold of 1-year mortality risk in patients with AAV by meta-analysis. More attention should be paid to the mortality risk of male patients with AAV in the early stage.

NLRP3, NLRC4 and NLRC5 Gene Polymorphisms Associate with Susceptibility of Pulmonary Aspergillosis in Non-Neutropenic Patients.

BACKGROUND: Non-neutropenic pulmonary aspergillosis is one of the most common and serious fungal infections. Previous studies have shown that single nucleotide polymorphisms (SNPs) of pattern recognition receptors genes are associated with susceptibility to aspergillosis. NOD-like receptors (NLRs) play an important role in the immunological response against fungal infection. In this study, we investigated the relationship between polymorphisms of three NLRs and susceptibility to pulmonary aspergillosis disease in non-neutropenic patients. METHODS: We included 73 patients with proven pulmonary aspergillosis and 103 healthy controls. A total of sixteen SNPs in the NLRP3, NLRC4, and NLRC5 genes were detected by PCR-direct sequencing. Then, we evaluated the association between these polymorphisms and susceptibility to aspergillosis. RESULTS: Fifteen SNPs were consistent with Hardy-Weinberg equilibrium except for NLRP3 rs7525979. A total of eight SNPs (NLRP3 rs3806265, NLRC4 rs212704 and NLRC5 rs1684579, rs12598522, rs3995817, rs3995818, rs34531240, rs28438857) were observed an association with susceptibility of pulmonary aspergillosis. The CC homozygote of NLRP3 rs3806265, TT homozygote of NLRC5 rs1684579 and T allele of NLRC5 rs12598522 were associated with a higher risk of aspergillosis while TT homozygote of NLRC4 rs212704 was associated with a lower risk of aspergillosis. Especially in the invasive pulmonary aspergillosis subgroup, the TT homozygote of NLRC5 rs1684579 and rs3995817, the CC homozygote of NLRC5 rs34531240 and rs28438857, GG homozygote of NLRC5 rs3995818, the C allele and CC homozygote of NLRP3 rs3806265 were associated with higher susceptibility. CONCLUSIONS: This study showed an association between polymorphisms of NLRP3, NLRC4, and NLRC5 and susceptibility to pulmonary aspergillosis for the first time. Further investigations in larger populations are needed, and functional studies are also required to investigate the function of these NLRs in aspergillosis, as well as other fungal infection diseases.

CCAAT/enhancer binding protein (C/EBP) delta promotes the expression of PTX3 and macrophage phagocytosis during A. fumigatus infection.

Given the increasing incidence of pulmonary aspergillosis, it is important to understand the natural defense mechanisms by which the body can kill Aspergillus fumigatus conidia. Pentraxin 3 (PTX3) plays a nonredundant role in resistance to A. fumigatus. Here, we found that the key predicted PTX3 transcription factor, CCAAT/enhancer-binding protein δ (CEBPD), was up-regulated during A. fumigatus conidia infection. Functionally, CEBPD significantly promoted the expression of PTX3 and the phagocytic ability of macrophages. Mechanistically, CEBPD activated the PTX3 by directly binding to the promoter region of the PTX3 gene. We also showed that the RNA-binding protein human antigen R promoted CEBPD expression. These findings provide new insights into the crucial role of CEBPD in the phagocytosis of A. fumigatus conidia by macrophages and highlight this protein as a potential therapeutic target for invasive pulmonary aspergillosis.

Clinical features of cryptococcosis in patients with different immune statuses: a multicenter study in Jiangsu Province-China.

BACKGROUND: Current guidelines support different management of cryptococcosis between severely immunodeficient and immunocompetent populations. However, few studies have focused on cryptococcosis patients with mild-to-moderate immunodeficiency. We performed this study to determine the clinical features of pulmonary (PC) and extrapulmonary cryptococcosis (EPC) and compared them among populations with different immune statuses to support appropriate clinical management of this public health threat. METHODS: All cases were reported by 14 tertiary teaching hospitals in Jiangsu Province, China from January 2013 to December 2018. The trends in incidence, demographic data, medical history, clinical symptoms, laboratory test indicators, imaging characteristics and diagnostic method of these patients were then stratified by immune status, namely immunocompetent (IC, patients with no recognized underlying disease or those with an underlying disease that does not influence immunity, such as hypertension), mild-to-moderate immunodeficiency (MID, patients with diabetes mellitus, end-stage liver or kidney disease, autoimmune diseases treated with low-dose glucocorticoid therapy, and cancer treated with chemotherapy) and severe immunodeficiency (SID, patients with acquired immunodeficiency syndrome, haematologic malignancies, solid organ transplantation or haematologic stem cell transplantation, idiopathic CD4 lymphocytosis, agranulocytosis, aggressive glucocorticoid or immunosuppressive therapy and other conditions or treatments that result in severe immunosuppression). RESULTS: The clinical data of 255 cryptococcosis patients were collected. In total, 66.3% of patients (169) were IC, 16.9% (43) had MID, and 16.9% (43) had SID. 10.1% of the patients (17) with IC were EPC, 18.6% of the patients (8) with MID were EPC, and 74.4% of patients (32) were EPC (IC/MID vs. SID, p < 0.001). Fever was more common in the SID group than in the IC and MID groups (69.8% vs. 14.8% vs. 37.2%, p < 0.001). Of chest CT scan, most lesions were distributed under the pleura (72.7%), presenting as nodules/lumps (90.3%) or consolidations (10.7%). Pleural effusion was more common in SID group compared to IC group (33.3% vs. 2.4%, p < 0.001). Positivity rate on the serum capsular polysaccharide antigen detection (CrAg) test was higher in the SID group than in the other two groups [100.0% vs. 84.4% (MID) vs. 78.2% (IC), p = 0.013]. Positivity rate on the serum CrAg test was also higher in cryptococcal meningitis patients than in PC patients (100.0% vs. 79.5%, p = 0.015). CONCLUSIONS: The clinical presentation of MID patients is intermediate between SID and IC patients and is similar to that of IC patients. The serum CrAg test is more sensitive for the identification of SID or EPC patients.

A risk-predictive model for invasive pulmonary aspergillosis in patients with acute exacerbation of chronic obstructive pulmonary disease.

OBJECTIVES: Invasive pulmonary aspergillosis (IPA) is increasingly reported in chronic obstructive pulmonary disease (COPD) patients. These patients often have poor clinical outcomes. Early recognition of IPA in COPD is always challenging. We aimed to develop and validate a risk model using readily available clinical parameters to predict IPA for acute exacerbation of COPD (AECOPD) patients. METHODS: We performed a retrospective cohort study. AECOPD patients who were admitted to Jinling Hospital between January 2012 and December 2017 were included. 880 AECOPD patients were randomly divided into the training set (70%, n = 616) and validation set (30%, n = 264). A nomogram model was developed using multivariate logistic regression from training set. The discrimination and calibration of model were validated internally. Decision curve analyses assessed the clinical utility of the nomogram. RESULTS: The incidence of IPA in hospitalized AECOPD patients was 9.6% in the training set (59 cases of IPA) and 9.1% in the validation set (24 cases of IPA), respectively. The nomogram model consisted of independent factors associated with IPA included lung function GOLD III-IV, use of broad-spectrum antibiotic over 10 days in the last month, oral or intravenous corticosteroids (prednisone) over 265 mg in the last 3 months and serum albumin < 30 g/L. The model performed good discrimination and calibration in validation set (c-statistic, 0.79 [95%CI 0.68-0.90]). The 95%CI region of calibration belt did not cross the 45-degree diagonal bisector line (P = 0.887). CONCLUSION: The simple risk predictive model for earlier recognition of IPA is useful in hospitalized AECOPD patients.

Serum anti-citrullinated protein antibodies and rheumatoid factor increase the risk of rheumatoid arthritis-related interstitial lung disease: a meta-analysis.

BACKGROUND: This meta-analysis aims to determine the association between antibodies including anti-citrullinated protein antibodies (ACPA) and rheumatoid factors (RF) and risk of rheumatoid arthritis-related interstitial lung disease (RA-ILD). METHODS: PubMed, Embase, and Cochrane were searched up to September 13, 2020, for studies investigating the risk of RA-ILD in ACPA-positive patients. The statistical meta-analysis and sensitivity analysis were performed using the Review Manager 5.4 and Stata16.0 software, respectively. RESULTS: Total 1 double-blind randomized controlled study and 16 observational studies, including 992 RA-ILD patients and 2223 RA-non ILD patients, met the inclusion criteria of the meta-analysis. Compared with ACPA-negative patients, positive serum ACPA increased the risk of RA-ILD (OR = 2.51; 95% CI: 1.35-4.68; P = 0.004) and serum ACPA titer was significantly correlated with risk of RA-ILD (SMD = 0.39; 95% CI: 0.17-0.62; P = 0.0006). In a region-based subgroup analysis, ACPA titer in Asian, European, and African populations was significantly related to the risk of RA-ILD, while there was no significant correlation in the Americans (SMD = - 0.03; 95% CI: - 0.89-0.83; P = 0.95), especially in the USA (SMD = 0.37; 95% CI: - 0.26-0.99; P = 0.25). In addition, serum positive RF increased the risk of RA-ILD (OR = 2.85; 95% CI: 2.19-3.71; P < 0.00001) and serum RF titer was significantly correlated with the risk of RA-ILD (SMD = 0.35; 95% CI: 0.23-0.46; P < 0.00001). However, for the analysis of RF dichotomous data, the funnel shape was asymmetric and the p value of egger test was less than 0.05, which indicated potential publication bias. CONCLUSIONS: ACPA and RF positive patients have greater risk of RA-ILD, and RA patients positive for ACPA should be paid more attention. KEY POINTS: • Autoantibodies ACPA and RF increase the risk of RA-ILD. • Regions may be related to RA-ILD.

Clinical features and prognostic analysis of patients with Aspergillus isolation during acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Lower respiratory tract (LRT) specimen culture is widely performed for the identification of Aspergillus. We investigated the clinical features and prognosis of patients with Aspergillus isolation from LRT specimens during acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: This is a 6-year single-center, real-world study. 75 cases out of 1131 hospitalized AECOPD patients were positive for Aspergillus. These patients were carefully evaluated and finally diagnosed of pulmonary aspergillosis (PA, 60 cases, 80%) or colonization (15 cases, 20%). Comparisons of clinical data were performed between these two groups. A cox regression model was used to confirm prognostic factors of Aspergillus infection. RESULTS: The PA group had worse lung function and higher rates of systemic corticosteroid use and broad-spectrum antibiotic use before admission than the colonization group. The PA group had significantly higher in-hospital mortality and 180-day mortality than the colonization group (45% (27/60) vs. 0% (0/15), p = 0.001, and 52.5% (31/59) vs. 6.7% (1/15), p < 0.001, respectively). By multivariable analysis among Aspergillus infection patients, antifungal therapy (HR 0.383, 95% CI 0.163-0.899, p = 0.027) was associated with improved survival, whereas accumulated dose of systemic steroids > 700 mg (HR 2.452, 95% CI 1.134-5.300, p = 0.023) and respiratory failure at admission (HR 5.983, 95% CI 2.487-14.397, p < 0.001) were independently associated with increased mortality. Significant survival differential was observed among PA patients without antifungals and antifungals initiated before and after Aspergillus positive culture (p = 0.001). CONCLUSIONS: Aspergillus isolation in hospitalized AECOPD patients largely indicated PA. AECOPD patients with PA had worse prognosis than those with Aspergillus colonization. Empirical antifungal therapy is warranted to improve the prognosis for Aspergillus infection.

MicroRNA-574-5p Attenuates Acute Respiratory Distress Syndrome by Targeting HMGB1.

Acute respiratory distress syndrome (ARDS) is a critical condition with high mortality. HMGB1 (high-mobility group protein B1) is one of the key proinflammatory factors in the ARDS "inflammatory storm." According to previous studies, some microRNAs (miRNAs) play important roles in this process. We aimed to determine the contributing miRNAs targeting the expression and release of HMGB1. miRNA expression in the peripheral blood of patients with ARDS was measured by miRNA microarray. miRNAs targeting HMGB1 were screened and explored for further study. In LPS-induced cell and mouse ARDS models, we explored the effect of this miRNA on the expression and secretion of HMGB1 by Western blot, real-time qPCR, and ELISA. The effects of this miRNA on the NF-κB signaling pathway, proinflammatory cytokines, and NLRP3 (nod-like receptor protein 3) inflammasome were detected by Western blot and real-time qPCR. In ARDS models, microRNA-574-5p (miR-574-5p) expression could be induced by the TLR4/NF-κB pathway upon LPS stimulation. It could suppress the inflammatory response by targeting HMGB1. Enforcing the expression of miR-574-5p or HMGB1 siRNA silencing inhibits the activation of NF-κB signaling pathway and the NLRP3 inflammasome. Moreover, overexpression of HMGB1 reversed the antiinflammatory effect of miR-574-5p. In ARDS mice, overexpression of miR-574-5p suppresses alveolar leukocytes infiltration, interstitial edema, protein effusion, and inflammation. This study demonstrated that miR-574-5p provided negative feedback to LPS-induced inflammation and relieved ARDS. It may provide new therapeutic strategies for ARDS.

Epidemiological Trends of Coronavirus Disease 2019 in China.

Background: The Coronavirus Disease 2019 (COVID-19) epidemic broke out in Wuhan, China, and it spread rapidly. Since January 23, 2020, China has launched a series of unusual and strict measures, including the lockdown of Wuhan city to contain this highly contagious disease. We collected the epidemiological data to analyze the trend of this epidemic in China. Methods: We closely tracked the Chinese and global official websites to collect the epidemiological information about COVID-19. The number of total and daily new confirmed cases of COVID-19 in China was presented to illustrate the trend of this epidemic. Results: On January 23, 2020, 835 confirmed COVID-19 cases were reported in China. On February 6, 2020, there were 31,211 cases. By February 20, 2020, the number reached as high as 75,993. Most cases were distributed in and around Wuhan, Hubei province. Since January 23, 2020, the number of daily new cases in China except Hubei province reached a peak of 890 on the eleventh day and then it declined to a low level of 34 within two full-length incubation periods (28 days), and the number of daily new cases in Hubei also started to decrease on the twelfth day, from 3,156 on February 4, 2020 to 955 on February 15, 2020. Conclusion: The COVID-19 epidemic has been primarily contained in China. The battle against this epidemic in China has provided valuable experiences for the rest of the world. Strict measures need to be taken as earlier as possible to prevent its spread.

The application of next-generation sequencing in diagnosing invasive pulmonary aspergillosis: three case reports.

Invasive pulmonary aspergillosis (IPA) is a severe infectious disease with high mortality. However, the clinical diagnosis of IPA remains difficult since the microbiological evidence is hard to acquire. The main issue of the current microbiological methods is that they are time-consuming and offer a low yield. Currently, next-generation sequencing (NGS) has become an attractive alternative method for broad-based pathogen discovery due to the rapid turnaround time and high accuracy. This article describes 3 cases of IPA. Two patients had a history of chronic obstructive pulmonary disease (COPD) and asthma, and the other patient had no underlying diseases. The Aspergillus fumigatus gene was found in the bronchoalveolar lavage fluid in all three cases by NGS. This report explores the role of NGS in the diagnosis of IPA and emphasizes that IPA may occur in non-neutropenic patients.