Real-world effectiveness and safety of nirmatrelvir-ritonavir (Paxlovid)-treated for COVID-19 patients with onset of more than 5 days: a retrospective cohort study.

Background: Nirmatrelvir-ritonavir (Paxlovid) has received emergency use authorization from the US Food and Drug Administration owing to its effectiveness and safety. However, data on the effectiveness and safety of Paxlovid use in COVID-19 patients with onset of more than 5 days are lacking. Methods: A real-world retrospective study was performed during the outbreak involving the SARS-CoV-2 BA.5.2 subvariant. Hospitalized COVID-19 patients (including mild, moderate, severe and critical cases) were divided into three groups: Paxlovid treatment within (Group A) or more than (Group B) 5 days of COVID-19 onset and no Paxlovid treatment during more than 5 days of COVID-19 onset with only basic symptomatic treatment (Group C). Endpoints were all-cause 28-day mortality, improvement in clinical classification, and a composite endpoint of disease progression, viral load and virus elimination time. Safety was assessed by comparing adverse events reported during treatment in each group. Results: During the period, 248 hospitalized COVID-19 patients, including 55 in Group A, 170 in Group B, and 23 in Group C, were enrolled. There were no significant differences in the clinical classification improvement rate [80.0% (16/20) vs. 81.3% (52/64), p = 1.000; 60.0% (21/35) vs. 55.7% (59/106), p = 0.653, respectively] or all-cause 28-day mortality [0% (0/20) vs. 1.6% (1/64), p = 1.000; 11.4% (4/35) vs. 6.6% (7/106), p = 0.576, respectively] between Groups A and B for nonsevere and severe cases. However, the clinical classification improvement rate in Group B was markedly higher than that in Group C [81.3% (52/64) vs. 50.0% (6/12), p = 0.049] among nonsevere cases. Cycle threshold values of the N and ORF genes in Group B were significantly increased after Paxlovid treatment [31.14 (IQR 26.81-33.93) vs. 38.14 (IQR 36.92-40.00), p < 0.001; 31.33 (IQR 26.00-33.47) vs. 38.62 (IQR 35.62-40.00), p < 0.001, respectively]. No significant differences in reported adverse events of neurological disease (p = 0.571), liver injury (p = 0.960) or kidney injury (p = 0.193) between Group A and Group B were found. Conclusion: Paxlovid treatment within 10 days of onset can shorten the disease course of COVID-19 by reducing the viral load. Paxlovid is effective and safe in treating COVID-19 with onset of more than five or even 10 days when patients have a high viral load.

Clinical and pathogen features of COVID-19-associated infections during an Omicron strain outbreak in Guangzhou, China.

Although the Omicron variant has been associated with greater transmissibility and tropism of the upper respiratory tract, the clinical and pathogenic features of patients infected with the Omicron variant during an outbreak in China have been unclear. Adults with COVID-19 were retrospectively enrolled from seven medical centers in Guangzhou, China, and clinical information and specimens ( BALF, sputum, and throat swabs) from participants were collected. Conventional detection methods, metagenomics next-generation sequencing (mNGS), and other methods were used to detect pathogens in lower respiratory tract samples. From December 2022 to January 2023, we enrolled 836 patients with COVID-19, among which 56.7% patients had severe/critical illness. About 91.4% of patients were infected with the Omicron strain (BA.5.2). The detection rate of possible co-infection pathogens was 53.4% by mNGS, including Klebsiella pneumoniae (16.3%), Aspergillus fumigatus (12.2%), and Pseudomonas aeruginosa (11.8%). The co-infection rate was 19.5%, with common pathogens being Streptococcus pneumoniae (11.5%), Haemophilus influenzae (9.2%), and Adenovirus (6.9%). The superinfection rate was 75.4%, with common pathogens such as Klebsiella pneumoniae (26.1%) and Pseudomonas aeruginosa (19.4%). Klebsiella pneumoniae (27.1%% vs 6.1%, P < 0.001), Aspergillus fumigatus (19.6% vs 5.3%, P = 0.001), Acinetobacter baumannii (18.7% vs 4.4%, P = 0.001), Pseudomonas aeruginosa (16.8% vs 7.0%, P = 0.024), Staphylococcus aureus (14.0% vs 5.3%, P = 0.027), and Streptococcus pneumoniae (0.9% vs 10.5%, P = 0.002) were more common in severe cases. Co-infection and superinfection of bacteria and fungi are common in patients with severe pneumonia associated with Omicron variant infection. Sequencing methods may aid in the diagnosis and differential diagnosis of pathogens. IMPORTANCE: Our study has analyzed the clinical characteristics and pathogen spectrum of the lower respiratory tract associated with co-infection or superinfection in Guangzhou during the outbreak of the Omicron strain, particularly after the relaxation of the epidemic prevention and control strategy in China. This study will likely prompt further research into the specific issue, which will benefit clinical practice.

Credibility of the evidence on green space and human health: an overview of meta-analyses using evidence grading approaches.

BACKGROUND: Green space is an important part of the human living environment, with many epidemiological studies estimating its impact on human health. However, no study has quantitatively assessed the credibility of the existing evidence, impeding their translations into policy decisions and hindering researchers from identifying new research gaps. This overview aims to evaluate and rank such evidence credibility. METHODS: Following the PRISMA guideline, we systematically searched PubMed, Web of Science, and Embase databases for systematic reviews with meta-analyses concerning green spaces and health outcomes published up to January 15, 2024. We categorized the credibility of meta-analytical evidence from interventional studies into four levels (i.e., high, moderate, low, and very low) using the Grading of Recommendation, Assessment, Development and Evaluations framework, based on five domains including risk of bias, inconsistency, indirectness, imprecision, and publication bias. Further, we recalculated all the meta-analyses from observational studies and classified evidence into five levels (i.e., convincing, highly suggestive, suggestive, weak, and non-significant) by considering stringent thresholds for P-values, sample size, robustness, heterogeneity, and testing for biases. FINDINGS: In total, 154 meta-analysed associations (interventional = 44, observational = 110) between green spaces and health outcomes were graded. Among meta-analyses from interventional studies, zero, four (wellbeing, systolic blood pressure, negative affect, and positive affect), 20, and 20 associations between green spaces and health outcomes were graded as high, moderate, low, and very low credibility evidence, respectively. Among meta-analyses from observational studies, one (cardiovascular disease mortality), four (prevalence/incidence of diabetes mellitus, preterm birth, and small for gestational age infant, and all-cause mortality), 12, 22, and 71 associations were categorized as convincing, highly suggestive, suggestive, weak, and non-significant evidence, respectively. INTERPRETATION: The current evidence largely confirms beneficial associations between green spaces and human health. However, only a small subset of these associations can be deemed to have a high or convincing credibility. Hence, future better designed primary studies and meta-analyses are still needed to provide higher quality evidence for informing health promotion strategies. FUNDING: The National Natural Science Foundation of China of China; the Guangzhou Science and Technology Program; the Guangdong Medical Science and Technology Research Fund; the Research Grant Council of the Hong Kong SAR; and Sino-German mobility program.

Improved diagnostic markers for invasive pulmonary aspergillosis in COPD patients.

Background: The prevalence of invasive pulmonary aspergillosis (IPA) among patients with chronic obstructive pulmonary disease (COPD) is steadily increasing, leading to high mortality. Although early diagnosis can significantly reduce mortality, the efficacy of current diagnostic methods is limited. Consequently, there is a need for novel approaches for early IPA detection. Methods: This retrospective study involved 383 hospitalized COPD patients with GOLD stages III and IV. The IPA group (67 patients) and non-IPA group (316 patients) were identified at the First Affiliated Hospital of Guangzhou Medical University between January 2016 and February 2022. We analyzed common serological indicators in our hospital to identify predictive indicators for the early diagnosis of IPA in COPD patients. Results: The sensitivity and specificity of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), lactate dehydrogenase (LDH), and ceruloplasmin (CER) for diagnosing IPA in COPD patients were as follows: CRP (91.2%, 57.7%), ESR (77.5%, 73.0%), PCT (60.5%, 71.4%), LDH (50.0%, 88.8%), and CER (60.7%, 74.3%). Combinations of biomarkers, such as CRP-ESR, CRP-LDH, ESR-LDH, ESR-CER, and LDH-CER, showed promising diagnostic potential, with larger area under the curve (AUC) values for IPA diagnosis in COPD patients. However, no statistically significant difference was observed between the diagnostic efficacy of single biomarkers and combined biomarkers. Notably, compared to those in the unassisted ventilation group, the patients in the assisted ventilation group (including noninvasive ventilation and tracheal intubation/incision-assisted ventilation group) exhibited significantly greater PCT and LDH levels, while the CER significantly decreased (p=0.021). There were no significant differences in biomarker levels between the ICU group and the non-ICU group. CRP (p<0.01), ESR (p=0.028), PCT (p<0.01), and CER (p<0.01) were positively correlated with hospitalization duration, whereas LDH was not correlated with hospitalization duration. Conclusion: Our study highlights the diagnostic potential of CRP, ESR, PCT, LDH, and CER for IPA in COPD patients. CRP and LDH can also initially predict the need for assisted ventilation, while CRP can initially estimate the length of hospitalization. This study represents the first report of the potential of CER for diagnosing IPA, suggesting its significance for further research.

Th1 cell immune response in Talaromyces marneffei infection with anti-interferon-γ autoantibody syndrome.

Anti-interferon-γ autoantibody (AIGA) syndrome may be the basis of disseminated Talaromyces marneffei infection in human immunodeficiency virus (HIV)-negative adults. However, the pathogenesis of Th1 cell immunity in T. marneffei infection with AIGA syndrome is unknown. A multicenter study of HIV-negative individuals with T. marneffei infection was conducted between September 2018 and September 2020 in Guangdong and Guangxi, China. Patients were divided into AIGA-positive (AP) and AIGA-negative (AN) groups according to the AIGA titer and neutralizing activity. The relationship between AIGA syndrome and Th1 immune deficiency was investigated by using AP patient serum and purification of AIGA. Fifty-five HIV-negative adults with disseminated T. marneffei infection who were otherwise healthy were included. The prevalence of AIGA positivity was 83.6%. Based on their AIGA status, 46 and 9 patients were assigned to the AP and AN groups, respectively. The levels of Th1 cells, IFN-γ, and T-bet were higher in T. marneffei-infected patients than in healthy controls. However, the levels of CD4+ T-cell STAT-1 phosphorylation (pSTAT1) and Th1 cells were lower in the AP group than in the AN group. Both the serum of patients with AIGA syndrome and the AIGA purified from the serum of patients with AIGA syndrome could reduce CD4+ T-cell pSTAT1, Th1 cell differentiation and T-bet mRNA, and protein expression. The Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients. Inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome.IMPORTANCEThe pathogenesis of Th1 cell immunity in Talaromyces marneffei infection with anti-interferon-γ autoantibody (AIGA) syndrome is unknown. This is an interesting study addressing an important knowledge gap regarding the pathogenesis of T. marneffei in non-HIV positive patients; in particular patients with AIGA. The finding of the Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients, and inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome, which presented in this research could help bridge the current knowledge gap.

Efficacy and safety of caspofungin for the treatment of invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

OBJECTIVES: We assessed the efficacy of a 3-week primary or salvage caspofungin regimen in patients with chronic obstructive pulmonary disease (COPD) and concomitant proven or suspected invasive pulmonary aspergillosis (IPA). METHODS: Forty-four patients were treated with an initial loading caspofungin dose of 70 mg, followed by a daily dose of 50 mg for 20 days. The main efficacy endpoint was clinical effectiveness. Secondary endpoints included the clinical efficacy of caspofungin after 1 week, therapeutic efficacy based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, the sensitivity of different Aspergillus strains to caspofungin in vitro, and the safety of caspofungin. RESULTS: An assessment of 42 patients in the intention-to-treat group revealed efficacy rates of 33.33% within 1 week and 38.10% within 3 weeks. According to the EORTC/MSG criteria, the treatment success rate was 38.10%. The success rate of first-line treatment was 54.76%, whereas salvage treatment had a success rate of 45.24%. No adverse events were reported among the participants. CONCLUSIONS: Caspofungin is effective and safe as an initial or salvage treatment for patients with IPA and COPD.

More attention should be paid to Omicron-associated sepsis: a multicenter retrospective study in south China.

Background: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible but causes less severe disease compared to other variants. However, its association with sepsis incidence and outcomes is unclear. This study aimed to investigate the incidence of Omicron-associated sepsis, as per the Sepsis 3.0 definition, in hospitalized patients, and to explore its relationship with clinical characteristics and prognosis. Methods: This multicenter retrospective study included adults hospitalized with confirmed SARS-CoV-2 infection across six tertiary hospitals in Guangzhou, China from November 2022 to January 2023. The Sequential Organ Failure Assessment (SOFA) score and its components were calculated at hospital admission to identify sepsis. Outcomes assessed were need for intensive care unit (ICU) transfer and mortality. Receiver operating characteristic curves evaluated the predictive value of sepsis versus other biomarkers for outcomes. Results: A total of 299 patients (mean age: 70.1±14.4 years, 42.14% female) with SOFA score were enrolled. Among them, 152 were categorized as non-serious cases while the others were assigned as the serious group. The proportion of male patients, unvaccinated patients, patients with comorbidity such as diabetes, chronic cardiovascular disease, and chronic lung disease was significantly higher in the serious than non-serious group. The median SOFA score of all enrolled patients was 1 (interquartile range, 0-18). In our study, 147 patients (64.19%) were identified as having sepsis upon hospital admission, with the majority of these septic patients (113, representing 76.87%) being in the serious group, the respiratory, coagulation, cardiovascular, central nervous, and renal organ SOFA scores were all significantly higher in the serious compared to the non-serious group. Among septic patients, 20 out of 49 (40.81%) had septic shock as indicated by lactate measurement within 24 hours of admission, and the majority of septic patients were in the serious group (17/20, 76.87%). Sepsis was present in 118 out of 269 (43.9%) patients in the general ward, and among those with sepsis, 34 out of 118 (28.8%) later required ICU care during hospitalization. By contrast, none of the patients without sepsis required ICU care. Moreover, the mortality rate was significantly higher in patients with than without sepsis. Conclusions: A considerable proportion of patients infected with Omicron present with sepsis upon hospital admission, which is associated with a poorer prognosis. Therefore, early recognition of viral sepsis by evaluation of the SOFA score in hospitalized coronavirus disease 2019 patients is crucial.

Safety and efficacy of onradivir in adults with acute uncomplicated influenza A infection: a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Onradivir (ZSP1273) is a novel anti-influenza A virus inhibitor. Preclinical studies show that onradivir can inhibit influenza A H1N1 and H3N2 replication and increase the survival rate of infected animals. In this study, we aimed to evaluate the safety and efficacy of three onradivir dosing regimens versus placebo in outpatients with acute uncomplicated influenza A virus infection. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial at 20 clinical sites in China. Eligible participants were adults (18-65 years) with an influenza-like illness screened by rapid antigen testing at the first clinical visit, had the presence of a fever (axillary temperature ≥38·0°C), and had the presence of at least one moderate systemic and one respiratory symptom within 48 h of symptom onset. Patients were excluded if they were pregnant, allergic to onradivir, or had received any influenza antiviral medication within 7 days before enrolment. Participants were randomly assigned (1:1:1:1) into four groups by an interactive web response system: onradivir 200 mg twice per day group, onradivir 400 mg twice per day group, onradivir 600 mg once per day group, and a matching placebo group. A 5-day oral treatment course was initiated within 48 h after symptoms onset. The primary outcome was the time to alleviate influenza symptoms in the modified intention-to-treat population. Safety was a secondary outcome. We evaluated the patients' self-assessed severity of seven influenza symptoms on a 4-point ordinal scale, and the treatment-emergent adverse events in all patients. This trial is registered with ClinicalTrials.gov, number NCT04024137. FINDINGS: Between Dec 7, 2019, and May 18, 2020, a total of 205 patients were screened; of whom, 172 (84%) were randomly assigned to receive onradivir (n=43 in the 200 mg twice per day group; n=43 in the 400 mg twice per day group; and n=43 in the 600 mg once per day group), or placebo (n=42). Median age was 22 years (IQR 20-26). All three onradivir groups showed decreased median time to alleviate influenza symptoms (46·92 h [IQR 24·00-81·38] in the 200 mg twice per day group, 54·87 h [23·67-110·62] in the 400 mg twice per day group, and 40·05 h [17·70-65·82] in the 600 mg once per day) compared with the placebo group (62·87 h [36·40-113·25]). The median difference between the onradivir 600 mg once per day group and the placebo group was -22·82 h (p=0·0330). The most frequently reported treatment-emergent adverse event was diarrhoea (71 [42%] of 171), ranging from 33-65% of the patients in onradivir-treated groups compared with 10% in the placebo group; no serious adverse events were observed. INTERPRETATION: Onradivir showed a safety profile comparable to placebo, as well as higher efficacy than placebo in ameliorating influenza symptoms and lowering the viral load in adult patients with uncomplicated influenza infection, especially the onradivir 600 mg once per day regimen. FUNDING: National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, National Natural Science Foundation of China, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project, Emergency Key Program of Guangzhou Laboratory, Macao Science and Technology Development Fund, and Guangdong Raynovent Biotech.

Defect engineering to tailor structure-activity relationship in biodegradable nanozymes for tumor therapy by dual-channel death strategies.

Pursuing biodegradable nanozymes capable of equipping structure-activity relationship provides new perspectives for tumor-specific therapy. A rapidly degradable nanozymes can address biosecurity concerns. However, it may also reduce the functional stability required for sustaining therapeutic activity. Herein, the defect engineering strategy is employed to fabricate Pt-doping MoOx (PMO) redox nanozymes with rapidly degradable characteristics, and then the PLGA-assembled PMO (PLGA@PMO) by microfluidics chip can settle the conflict between sustaining therapeutic activity and rapid degradability. Density functional theory describes that Pt-doping enables PMO nanozymes to exhibit an excellent multienzyme-mimicking catalytic activity originating from synergistic catalysis center construction with the interaction of Pt substitution and oxygen vacancy defects. The peroxidase- (POD), oxidase- (OXD), glutathione peroxidase- (GSH-Px), and catalase- (CAT) mimicking activities can induce robust ROS output and endogenous glutathione depletion under tumor microenvironment (TME) response, thereby causing ferroptosis in tumor cells by the accumulation of lipid peroxide and inactivation of glutathione peroxidase 4. Due to the activated surface plasmon resonance effect, the PMO nanozymes can cause hyperthermia-induced apoptosis through 1064 nm laser irradiation, and augment multienzyme-mimicking catalytic activity. This work represents a potential biological application for the development of therapeutic strategy for dual-channel death via hyperthermia-augmented enzyme-mimicking nanocatalytic therapy.

Pulmonary cryptococcosis complicated with pulmonary aspergillosis: a series of studies and a literature review.

BACKGROUND/OBJECTIVE: With the development of society, pulmonary fungal diseases, represented by pulmonary aspergillosis and pulmonary cryptococcosis, have become increasingly common. However, there is a lack of clear understanding regarding coinfection by these two types of fungi in immunocompetent individuals. METHODS: A retrospective study from 2014 to 2022 and a systematic literature review of original articles published in English were performed. Patients with pulmonary cryptococcosis complicated with pulmonary aspergillosis including 5 in the retrospective study and 6 in the systematic literature review. RESULT: The diagnosis of concurrent pulmonary cryptococcosis and pulmonary aspergillosis in patients was confirmed through repeated biopsies or surgical resection. Pulmonary cryptococcosis is often diagnosed initially (6/11, 55%), while the diagnosis of pulmonary aspergillosis is established when the lesions become fixed or enlarged during treatment. Transbronchial lung biopsy (3/11, 27%), thoracoscopic lung biopsy (2/11, 18%), and percutaneous aspiration biopsy of the lung (1/11, 9%) were the main methods to confirm concurrent infection. Most patients were treated with voriconazole, resulting in a cure for the coinfection (6/11, 55%). CONCLUSION: Pulmonary cryptococcosis complicated with pulmonary Aspergillus is an easily neglected mixed fungal infection. During the treatment of lesion enlargement in clinical cryptococcus, we need to watch out for Aspergillus infection.

Subacute infective endocarditis due to Lodderomyces elongisporus: a case report and review of the literature.

Lodderomyces elongisporus, a rare emerging pathogen, can cause fungemia often related to immunosuppression or intravenous devices. Herein, we report the case of a 58-year-old woman with subacute infective endocarditis due to Lodderomyces elongisporus identified by blood fungal culture and whole-genome sequencing, who was treated with antifungals, mitral replacement and endocardial vegetation removal surgery.

Serum sphingolipids aid in diagnosing adult HIV-negative patients with pulmonary cryptococcosis: a clinical cohort study.

Background: Pulmonary cryptococcosis (PC) contributes to the ongoing global disease burden in human immunodeficiency virus (HIV)-negative populations. Since some PC patients are misdiagnosed under existing diagnostic guidelines, new diagnostic markers are needed to improve diagnostic accuracy and therapeutic efficacy and reduce disease risk. Methods: Our previously established sphingolipidomic approach was employed to explore the use of serum sphingolipids (SPLs) in diagnosing HIV-negative patients with PC. A clinical cohort of PC, pulmonary aspergillosis (PA), and tuberculosis (TB) patients and healthy controls was assessed to identify SPL biomarkers. Results: A total of 47 PC, 27 PA, and 18 TB patients and 40 controls were enrolled. PC and TB patients had similar clinical features, laboratory test results and radiological features, excluding plural effusion. The serum ceramide [Cer (d18:1/18:0)] level showed a significant increase in PC patients compared to controls and PA and TB patients (P<0.05). Cer (d18:1/18:0) was identified as a specific diagnostic biomarker for PC. The optimal cut-off value of greater than 18.00 nM showed a diagnostic sensitivity of 76.60% and a specificity of 95.00% and better distinguished PC patients from PA and TB patients. Furthermore, the serum Cer (d18:1/18:0) level gradually decreased after 3 and 6 months of treatment, suggesting the prediction potential for therapeutic efficacy of this biomarker. In addition, Cer (d18:1/18:0) analysis presented a higher sensitivity than the cryptococcal antigen (CrAg) assay. Conclusions: This is the first study to report the use of the SPL Cer (d18:1/18:0) as a serum biomarker for diagnosing Cryptococcus spp. infection in HIV-negative patients.

Comparison of diagnostic efficiency of detecting IgG and IgE with immunoassay method in diagnosing ABPA: a meta-analysis.

BACKGROUND: Hitherto, the bulk of diagnostic criteria regards Aspergillus-specific immunoglobulin E as a key item, and regard IgG as an auxiliary method in diagnose. Nevertheless, there is no conclusive study in summarize the performance of IgG and IgE diagnosing ABPA. METHODS: We conducted a systematic review to identify studies report results of IgE and IgG detection in diagnosing ABPA. QUADAS-2 tool was used to evaluate included studies, and we applied the HSROC model to calculate the pooled sensitivity and specificity. Deeks' funnel was derived to evaluated the public bias of included studies, and Cochrane Q test and I2 statistic were used to test the heterogeneity. RESULTS: Eleven studies were included in this study (1127 subjects and 215 for IgE and IgG). Deeks's test for IgE and IgG were 0.10 and 0.19. The pooled sensitivity and specificity for IgE were 0.83 (95%CI: 0.77, 0.90) and 0.89 (0.83, 0.94), and for IgG were 0.93 (0.87, 0.97) and 0.73 (0.62,0.82), with P value < 0.001. The PLR and NLR for IgE were 7.80 (5.03,12.10) and 0.19 (0.13,0.27), while for IgG were 3.45 (2.40,4.96) and 0.09 (0.05,0.17). The combined diagnostic odds ratio and diagnostic score were 41.49 (26.74,64.36) and3.73 (3.29,4.16) for IgE, respectively, and were 38.42 (19.23,76.79) and 3.65 (2.96,4.34) for IgG. CONCLUSION: The sensitivity for IgG diagnosing ABPA is higher than IgE, while the specificity for IgE is higher. IgG might be able to play a more important role in filtering ABPA patients.

Comparison of the clinical features of HIV-positive and HIV-negative hosts infected with Talaromyces marneffei: A multicenter, retrospective study.

OBJECTIVES: Talaromyces marneffei is an emerging pathogen, and the number of infections in HIV-negative individuals is rapidly increasing. Nevertheless, there is no sufficient comprehensive report on this issue, and awareness needs to be raised among clinicians. METHODS: We analyzed the differences in the clinical data of patients who are HIV-negative and HIV-positive with Talaromyces marneffei infection (TMI) from 2018 to 2022. RESULTS: A total of 848 patients were included, among whom 104 were HIV-negative. The obvious differences between the HIV-positive and HIV-negative groups were as follows: (i) the patients who are HIV-negative were older and more likely to exhibit cough and rash, (ii) the time in days from symptom onset to diagnosis among patients who are HIV-negative was longer, (iii) the laboratory findings and radiological presentations seemed more severe in patients who are HIV-negative, (iv) differences were observed regarding the underlying conditions and co-infection pathogens, and correlation analysis showed that correlations existed for many indicators, (v) and persistent infection was more likely to occur in patients who are HIV-negative. CONCLUSION: TMI in patients who are HIV-negative differs from that in patients who are HIV-positive in many aspects, and more investigations are needed. Clinicians should be more aware of TMI in patients who are HIV-negative.

Disseminated Talaromyces marneffei Infection With STAT3-Hyper-IgE Syndrome: A Case Series and Literature Review.

Background: Little is known about the clinical characteristics of talaromycosis with hyper-immunoglobulin E syndrome (HIES). Methods: We conducted a multicenter retrospective study, which included 7 hospitals from 2016 to 2022. Five consecutive cases of human immunodeficiency virus (HIV)-negative patients with systemic Talaromyces marneffei infections due to STAT3-HIES were identified. A systematic literature review of original articles published in English identified an additional 7 cases. Clinical characteristics and laboratory parameters were collected. Results: Forty-two percent (5/12) of patients were young adults. The main symptoms of 10 patients were similar: fever (75%), cough (75%) and dyspnea (33%), but two patients mainly had gastrointestinal symptoms. Most patients had a history of infections since infancy. T marneffei was cultured from the bronchoalveolar lavage fluid (50%) and 25% of patients were next-generation sequencing positive. Eight patients had significantly elevated serum immunoglobulin E, increased B cells and decreased natural killer cells. There were ten different STAT3 mutations, three of which were reported for the first time in this study. Chest computed tomography examinations showed multiple exudations with cavities in the lungs. Voriconazole combined with thymosin was effective. Despite given antifungal agents, most had poor outcomes and the case fatality rate was as high as 25%. Conclusions: STAT3-HIES is most likely a susceptibility factor for T marneffei infections among HIV-negative patients, which has a high case fatality rate. Increased awareness among clinicians is necessary to help in early diagnosis.

Prevention of exacerbation in patients with moderate-to-very severe COPD with the intent to modulate respiratory microbiome: a pilot prospective, multi-center, randomized controlled trial.

Introduction: Considering the role of bacteria in the onset of acute exacerbation of COPD (AECOPD), we hypothesized that the use of influenza-Streptococcus pneumoniae vaccination, oral probiotics or inhaled amikacin could prevent AECOPD. Methods: In this pilot prospective, muti-central, randomized trial, moderate-to-very severe COPD subjects with a history of moderate-to-severe exacerbations in the previous year were enrolled and assigned in a ratio of 1:1:1:1 into 4 groups. All participants were managed based on the conventional treatment recommended by GOLD 2019 report for 3 months, with three groups receiving additional treatment of inhaled amikacin (0.4 g twice daily, 5-7 days monthly for 3 months), oral probiotic Lactobacillus rhamnosus GG (1 tablet daily for 3 months), or influenza-S. pneumoniae vaccination. The primary endpoint was time to the next onset of moderate-to-severe AECOPD from enrollment. Secondary endpoints included CAT score, mMRC score, adverse events, and survival in 12 months. Results: Among all 112 analyzed subjects (101 males, 96 smokers or ex-smokers, mean ± SD age 67.19 ± 7.39 years, FEV1 41.06 ± 16.09% predicted), those who were given dual vaccination (239.7 vs. 198.2 days, p = 0.044, 95%CI [0.85, 82.13]) and oral probiotics (248.8 vs. 198.2 days, p = 0.017, 95%CI [7.49, 93.59]) had significantly delayed onset of next moderate-to-severe AECOPD than those received conventional treatment only. For subjects with high symptom burden, the exacerbations were significantly delayed in inhaled amikacin group as compared to the conventional treatment group (237.3 vs. 179.1 days, p = 0.009, 95%CI [12.40,104.04]). The three interventions seemed to be safe and well tolerated for patient with stable COPD. Conclusion: The influenza-S. pneumoniae vaccine and long-term oral probiotic LGG can significantly delay the next moderate-to-severe AECOPD. Periodically amikacin inhalation seems to work in symptomatic patients. The findings in the current study warrants validation in future studies with microbiome investigation.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT03449459.

Allicin shows antifungal efficacy against Cryptococcus neoformans by blocking the fungal cell membrane.

Allicin, which is generated by the catalytic reaction between alliin and alliinase extracted from garlic, has been shown to have a wide range of antimicrobial activities, but its anti-Cryptococcus efficacy and mechanism are not quite clear. Here, we have determined that the Conversion rate of allicin in the reaction product reached 97.5%. The minimal inhibitory concentration (MIC) of allicin against Cryptococcus neoformans (C. neoformans) H99 was 2 µg/ml, which is comparable to fluconazole (FLU, 1 µg/ml). Furthermore, allicin exhibited effective antifungal activity against 46 clinical isolates of C. neoformans, and the MICs ranged from 1 to 8 µg/ml, even for AmB-insensitive strains. Interestingly, allicin also exerted additive or synergistic effects when combined with amphotericin B (AmB) and FLU. Time-killing curves and long-term live cell imaging of H99 showed that 4 MIC of allicin had fungicide activity. Additionally, allicin (4 and 8 mg/kg) exerted a dose-dependent therapeutic effect on H99-infected mice by significantly reducing the wet pulmonary coefficient and Cryptococcus load and reducing lung damage. Even the efficacy of 8 mg/kg was comparable to FLU (20 mg/kg). Transcriptomics revealed that allicin may act on the cell membrane of H99. Subsequently, transmission electron microscopy (TEM) observations showed that allicin clearly breached the cell membrane and organelles of H99. Confocal laser scanning microscopy (CLSM) results further confirmed that allicin disrupted the permeability of the cell membranes of H99 in a dose-dependent manner. Allicin exhibits strong anti-C. neoformans activity in vitro and in vivo, mainly by destroying the permeability and related functions of Cryptococcus cell membranes.

Loss to follow-up associated factors in patients with chronic pulmonary aspergillosis and its impact on the disease prognosis.

Objective: Pulmonary aspergillosis is a rare but challenging pulmonary disease. The conditions of patients with chronic pulmonary aspergillosis (CPA) can be even more complicated. The mortality rate of CPA remains high, and the prognostic factors are not well established due to a high proportion of loss to follow-up. In this study, we aim to explore factors associated with loss to follow-up in CPA patients and their impact on the disease prognosis after withdrawing anti-fungal treatments. Methods: Patients with confirmed CPA, who were admitted to the Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Guangzhou Medical University from March 2017 to November 2019, were enrolled in this prospective study. The enrolled patients were followed up for 6 months after discharge. For loss to follow-up patients, the reasons for loss to follow-up and their prognosis after withdrawing anti-fungal treatments during loss to follow-up were recorded by telephone communication. Multivariate logistic regression analysis was performed to determine factors associated with loss to follow-up. Results: The 199 out of 298 screened patients were included in the study. Except for 67 cases with regular follow-up, the rest 132 cases were lost to follow-up. Factors, including age > 60 years (OR = 2.036, P = 0.03), monthly income ≤ $583 (OR = 5.568, P = 0.0001), education ≤ 6 years (OR = 7.474, P = 0.0001), and non-local residence (OR = 5.893, P = 0.0001) were associated with the loss to follow-up according to multivariate logistic regression analysis. The most common reasons for loss to follow-up were economic factors and clinic visit distance. The overall case fatality rate (CFR) within 180 days in patients with regular follow-up and patients who stopped anti-fungal treatment during the loss to follow-up was 0% and 19.65%, respectively. Conclusion: The proportion of loss to follow-up in CPA patients remained high. Age (>60 years), poor financial status, low education, and non-local residence were the key factors associated with the loss to follow-up in this study. Our study reveals the need to optimize the follow-up procedures and improve the patients understanding about the benefits and limitations of follow-up to reduce the CFR.

Pathogen spectrum and immunotherapy in patients with anti-IFN-γ autoantibodies: A multicenter retrospective study and systematic review.

Background: Anti-interferon-γ autoantibody (AIGA) positivity is an emerging immunodeficiency syndrome closely associated with intracellular infection in individuals without human immunodeficiency virus (HIV). However, the information on epidemiology, pathogen spectrum, and immunotherapy among these patients lack a systematic description of large data. Methods: This systematic literature review and multicenter retrospective study aimed to describe the pathogen spectrum and review treatment strategies among patients with AIGA positivity. Results: We included 810 HIV-negative patients with AIGA positivity infected with one or more intracellular pathogens. Excluding four teenagers, all the patients were adults. The most common pathogen was nontuberculous mycobacteria (NTM) (676/810, 83.5%). A total of 765 NTM isolates were identified in 676 patients with NTM, including 342 (44.7%) rapid-grower mycobacteria, 273 (35.7%) slow-grower mycobacteria, and 150 (19.6%) unidentified NTM subtype. Even with long-term and intensive antimicrobial treatments, 42.6% of patients with AIGA positivity had recurrence and/or persistent infection. Sixty-seven patients underwent immunoregulatory or immunosuppressive therapy, and most (60) achieved remission. The most common treatment strategy was rituximab (27/67, 40.3%) and cyclophosphamide (22/67, 32.8%), followed by cyclophosphamide combined with glucocorticoids (8/67, 11.9%). Conclusions: Intracellular pathogen was the most common infection in patients with AIGA positivity. The predominant infection phenotypes were NTM, varicella-zoster virus, Talaromyces marneffei, and Salmonella spp., with or without other opportunistic infections. AIGA immunotherapy, including rituximab or cyclophosphamide, has yielded good preliminary results in some cases.

Development and clinical application of an electronic health record quality control system for pulmonary aspergillosis based on guidelines and natural language processing technology.

Background: There are considerable differences in the diagnosis and treatment of pulmonary aspergillosis (PA) between specialized hospitals and primary hospitals or developed areas and underdeveloped areas in China. There is a lack of electronic systems that assist respiratory physicians in standardizing the diagnosis and treatment of PA. Methods: We extracted 26 quality control points from the latest guidelines related to PA, and developed a PA quality control system of electronic health record (EHR) based on natural language processing (NLP) techniques. We obtained PA patient records in the Department of Respiratory Medicine of the First Affiliated Hospital of Guangzhou Medical University to verify the effectiveness of the system comparing with manually evaluation of respiratory experts. Results: We successfully developed quality control system of PA; 699 PA medical records from EHR of the First Affiliated Hospital of Guangzhou Medical University between January 2015 and March 2020 were obtained and assessed by the system; 162 defects were found, which included 19 medical records with diagnostic defects, 76 medical records with examination defects, and 80 medical records with treatment defects; 200 medical records were sampled for validation, and found that the sensitivity and accuracy of quality control system for pulmonary aspergillosis (QCSA) were 0.99 and 0.96, F1 value was 0.85, and the recall rate was 0.77 compared with experts' evaluation. Conclusions: Our system successfully uses medical guidelines and NLP technology to detect defects in the diagnosis and treatment of PA, which helps to improve the management quality of PA patients.