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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.
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Aspergilosis , Coinfección , Criptococosis , Aspergilosis Pulmonar , Humanos , Coinfección/complicaciones , Estudios Retrospectivos , Aspergilosis Pulmonar/complicaciones , Aspergilosis Pulmonar/diagnóstico , Criptococosis/complicaciones , Criptococosis/diagnóstico , Criptococosis/tratamiento farmacológico , Aspergilosis/diagnósticoRESUMEN
BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .
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COVID-19 , Medicamentos Herbarios Chinos , Adulto , Humanos , Método Doble Ciego , Medicamentos Herbarios Chinos/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Etiological diagnosis is a key step in the treatment of patients with rare pulmonary mycosis, and the lack of understanding of this disease and lack of specific markers for the detection of rare species, such as Exophiala dermatitidis, add to the difficulty in diagnosing the condition. Therefore, improving the diagnostic strategies for this disease is very important. CASE PRESENTATION: A 52-year-old man presented with cough, sputum production and hemoptysis; chest computed tomography (CT) revealed multiple bilateral lesions. The pathogen was unable to be identified after three biopsies. Subsequently, we performed combined tissue metagenomic next-generation sequencing (mNGS). The results of mNGS and a good therapeutic response helped to identify the causative pathogen as Exophiala dermatitidis. Finally, the patient was diagnosed with Exophiala dermatitidis pneumonia. CONCLUSIONS: Combining molecular techniques, such as mNGS, with clinical microbiological tests will improve the rate of positivity in the diagnosis of rare fungal infections, and the importance of follow-up should be emphasized.
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Exophiala , Micosis , Neumonía , Biopsia , Exophiala/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The eicosanoid metabolic pathway is responsible for mediating the production of various inflammatory factors that are closely related to the development and resolution of inflammation. In biological matrices, the major quantifying obstacles were shown to be the oxidation and low quantities of eicosanoids and their metabolites. This study aimed to develop a reliable, sensitive ultrahigh-performance liquid chromatography coupled to a tandem mass spectrometry (UPLC-MS/MS) method to quantify eicosanoids in human serum. Solid-phase extraction (SPE) was used for sample preparation. The approach employed continuous ionization polarity switching. The target eicosanoids showed good linearity over the investigated concentration range (r2 > 0.99). The recovery rates were over 64.5%, and the matrix effects ranged from 73.0 to 128.0%. The limits of quantification were 0.048 ~ 0.44 ng/mL. For the broad concentration range, the CV % for accuracy and precision were less than ± 20%. We successfully applied this method to rapidly analyse 74 serum samples from severe influenza pneumonia, severe bacterial pneumonia and healthy individuals. Eicosanoid-related metabolite concentrations were quantified within a range similar to those of previously published articles. Compared to healthy individuals, our application found that 20-HETE, 14,15-EET and 11,12-EET were upregulated in severe influenza pneumonia patients, while LTB4 was downregulated. 8-HETE and 5-HETE were upregulated in severe bacterial pneumonia patients, while LTE4 was downregulated. This approach provides a means for monitoring the low quantities of eicosanoids in biological matrices, and our finding that different characteristic metabolite profiles may help discriminate the induction of severe pneumonia patients.
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Gripe Humana , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida/métodos , Cromatografía Líquida de Alta Presión/métodos , Eicosanoides/metabolismo , Extracción en Fase SólidaRESUMEN
BACKGROUND: Talaromyces marneffei (T. marneffei) infection has been associated with adult-onset immunodeficiency due to anti-IFN-γ autoantibodies. We aimed to investigate the clinical features of non-HIV-infected patients with T. marneffei infection in southern China. METHODS: Between January 2018 and September 2020, we enrolled patients with T. marneffei infection who were HIV-negative (group TM, n = 42), including anti-IFN-γ autoantibody-positive (group TMP, n = 22) and anti-IFN-γ autoantibody-negative (group TMN, n = 20) patients and healthy controls (group HC, n = 40). Anti-IFN-γ autoantibodies were detected by ELISA. Clinical characteristics and clinical laboratory parameters were recorded. RESULTS: Compared with anti-IFN-γ autoantibody-negative patients with T. marneffei infection, anti-IFN-γ autoantibody-positive patients did not have underlying respiratory disease; more frequently exhibited dissemination of systemic infections with severe pleural effusion; had higher WBC counts, C-reactive protein levels, erythrocyte sedimentation rates, and neutrophil and CD8+ T cell counts; had lower hemoglobin levels; and were more likely to have other intracellular pathogen infections. Most of these patients had poor outcomes despite standardized antimicrobial therapy. CONCLUSION: T. marneffei-infected patients with higher anti-IFN-γ autoantibody titers have more severe disease and complex clinical conditions.
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Síndromes de Inmunodeficiencia/etiología , Interferón gamma/inmunología , Micosis/inmunología , Adulto , Autoanticuerpos/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la EnfermedadAsunto(s)
COVID-19/epidemiología , Coinfección/epidemiología , Virosis/epidemiología , Adulto , Anciano , Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/virología , China/epidemiología , Coinfección/microbiología , Coinfección/virología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The epidemiological and evolutionary dynamics of the two cocirculating lineages of influenza B virus, Victoria and Yamagata, are poorly understood, especially in tropical or subtropical areas of Southeast Asia. We performed a phylogenetic analysis of the hemagglutinin (HA) and neuraminidase (NA) sequences of influenza B viruses isolated in Guangzhou, a southern Chinese city, during 2009 to 2010 and compared the demographic and clinical features of infected patients. We identified multiple viral introductions of Victoria strains from both Chinese and international sources, which formed two phylogenetically and antigenically distinct clades (Victoria 1 and 2), some of which persisted between seasons. We identified one dominant Yamagata introduction from outside China during 2009. Our phylogenetic analysis reveals the occurrence of reassortment events among the Victoria and Yamagata lineages and also within the Victoria lineage. We found no significant difference in clinical severity by influenza B lineage, with the exceptions that (i) the Yamagata lineage infected older people than either Victoria lineage and (ii) fewer upper respiratory tract infections were caused by the Victoria 2 than the Victoria 1 clade. Overall, our study reveals the complex epidemiological dynamics of different influenza B lineages within a single geographic locality and has implications for vaccination policy in southern China.
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Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Virus de la Influenza B/clasificación , Virus de la Influenza B/aislamiento & purificación , Gripe Humana/epidemiología , Neuraminidasa/genética , Filogenia , Adolescente , Adulto , Evolución Biológica , China/epidemiología , Femenino , Humanos , Virus de la Influenza B/genética , Gripe Humana/genética , Gripe Humana/virología , Masculino , Epidemiología Molecular , ARN Viral/genética , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
BACKGROUND: Viral pathogens were more commonly reported than previously estimated in community-acquired pneumonia (CAP) patients. However, the real role of virus was still controversial. METHODS: Consecutive adult patients with CAP between April and December, 2009 were prospectively enrolled. A four-fold or greater increase of IgG-titres against respiratory viruses in pair sera was tested by means of hemagglutination inhibition assay or indirect immunofluorescence. Swab samples were tested by cell culture and/or nucleic amplification tests. Viral etiology was considered definitive if at least one of the above tests was positive. RESULTS: Viral etiology was established in fifty-two (34.9%) of 149 CAP patients, twenty-two (81.5%) of 27 influenza like illness patients, and none of 75 volunteer controls. Forty-seven CAP patients were infected by a single virus (24 influenza A virus, 5 influenza B, 10 parainfluenza virus type 3 [PIV-3], 2 PIV-1, 2 adenovirus, 2 human rhinovirus and 2 coronavirus OC43), five cases by two or three viruses co-infection. Fever ≥ 39 °C (66.7%), fatigue (64.6%), and purulent sputum (52.1%) was the most common symptoms in viral pneumonia patients. On multivariate analysis, myalgia was included in the model for pneumonia associated with influenza infection. In the CURB-65 model only influenza infection was found independently associated with severe disease (CURB-65 score ≥ 3) out of variables, including age(years), sex, current smoking status, sick contact with febrile patients, numbers of comorbidity, presence of influenza infection, presence of PIV infection, with P = 0.021, OR 7.86 (95% CI 1.37-45.04). CONCLUSION: Respiratory virus was not a bystander, but pathogenic in pneumonia and was a common cause of CAP.
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Infecciones por Adenoviridae/virología , Anticuerpos Antivirales/sangre , Inmunoglobulina G/sangre , Neumonía Viral/virología , Infecciones por Virus ARN/virología , Adenoviridae/inmunología , Infecciones por Adenoviridae/sangre , Adulto , Anciano , Coinfección/virología , Infecciones Comunitarias Adquiridas/sangre , Infecciones Comunitarias Adquiridas/virología , Coronavirus/inmunología , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/virología , Femenino , Voluntarios Sanos , Humanos , Virus de la Influenza A/inmunología , Virus de la Influenza B/inmunología , Gripe Humana/sangre , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Virus de la Parainfluenza 1 Humana/inmunología , Virus de la Parainfluenza 3 Humana/inmunología , Infecciones por Picornaviridae/sangre , Infecciones por Picornaviridae/virología , Neumonía Viral/sangre , Estudios Prospectivos , Infecciones por Virus ARN/sangre , Infecciones por Respirovirus/sangre , Infecciones por Respirovirus/virología , Rhinovirus/inmunologíaRESUMEN
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.
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Aspergilosis , Aspergilosis Pulmonar Invasiva , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Caspofungina/uso terapéutico , Aspergilosis Pulmonar Invasiva/complicaciones , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/inducido químicamente , Antifúngicos/efectos adversos , Equinocandinas/efectos adversos , Lipopéptidos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológicoRESUMEN
BACKGROUND: Reducing current clinical symptoms and the risks of future exacerbations is the main goal of stable COPD management. Traditional Chinese medicine has unique advantages in chronic disease management. YuPingFeng (YPF), as a classical prescription, has been proven to reduce the risk of exacerbations, but there is a lack of high-quality evidence for the assessment of clinical symptoms and quality of life, particularly for the assessment of treatment response of microecology and immunity. METHODS/DESIGN: This is a prospective, multicentre, randomized, double-blind, placebo-controlled clinical trial. A total of 316 eligible subjects with moderate to severe COPD will be randomized 1:1 to receive YPF or placebo. Participants will receive either YPF or a placebo at 5 g three times daily for 52 weeks. The primary outcome will be the change in the COPD Assessment Test (CAT) score after 52 weeks of treatment. Secondary outcomes will include changes in the St George's Respiratory Questionnaire (SGRQ) score and clinical symptom score, among others. Outcomes will be measured at each visit. The study will continue for 52 weeks and will include six visits to each subject (at day 0 and weeks 4,12,24,36 and 52). In the event of exacerbations, subjects will be required to go back to the hospital once on the first day of exacerbation or when their condition permits. DISCUSSION: This trial will provide research methods to evaluate the clinical efficacy, safety, and the possible mechanism of YPF in the treatment of stable moderate-to-severe COPD patients. In addition, we hope to provide more possibilities for TCM to participate in the management of stable COPD. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trials Registry on 3 June 2022 (ChiCTR2200060476; date recorded: 3/6/2022, https://www.chictr.org.cn/ ).
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Enfermedad Pulmonar Obstructiva Crónica , Calidad de Vida , Humanos , Estudios Prospectivos , Método Doble Ciego , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
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.
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Aspergilosis Pulmonar Invasiva , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Estudios Retrospectivos , Proteína C-Reactiva/análisis , Biomarcadores , Polipéptido alfa Relacionado con CalcitoninaRESUMEN
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.
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Antivirales , Gripe Humana , Humanos , Gripe Humana/tratamiento farmacológico , Adulto , Masculino , Método Doble Ciego , Femenino , Persona de Mediana Edad , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Antivirales/efectos adversos , Adulto Joven , Adolescente , Anciano , Resultado del Tratamiento , China , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacosRESUMEN
Background: Accurate detection of influenza virus in clinical samples requires correct execution of all aspects of the detection test. If the viral load in a sample is below the detection limit, a false negative result may be obtained. To overcome this issue, we developed a modified transport medium (MTM) for clinical sample transportation to increase viral detection sensitivity. Method: We first validated the MTM using laboratory-stocked influenza A viruses (IAVs: H1N1, H3N2, H7N3, H9N2) and influenza B viruses (IBVs: Yamagata, Victoria). We also tested clinical samples. A total of 110 patients were enrolled and a pair of samples were collected to determine the sensitivity of real-time polymerase chain reaction (RT-PCR) following MTM treatment. Result: After 24 h culturing in MTM, the viral loads were increased, represented by a 10-fold increase in detection sensitivity for H1N1, H9N2, and IBVs, a 100-fold increase for H3N2, and a 1,000-fold increase for H7N3. We further tested the effects of MTM on 19 IAV and 11 IBV stored clinical samples. The RT-PCR results showed that the positive detection rate of IAV samples increased from 63.16% (12/19) without MTM culturing to 78.95% (15/19) after 48 h culturing, and finally 89.47% (17/19) after 72 h culturing. MTM treatment of IBV clinical samples also increased the positive detection rate from 36.36% (4/11, 0 h) to 63.64% (7/11, 48 h) to 72.73% (8/11, 72 h). For clinical samples detected by RT-PCR, MTM outperformed other transport mediums in terms of viral detection rate (11.81% increase, P=0.007). Conclusion: Our results demonstrated that the use of MTM for clinical applications can increase detection sensitivity, thus facilitating the accurate diagnosis of influenza infection.
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Virus de la Influenza A , Virus de la Influenza B , Gripe Humana , Sensibilidad y Especificidad , Manejo de Especímenes , Carga Viral , Humanos , Gripe Humana/diagnóstico , Gripe Humana/virología , Virus de la Influenza A/aislamiento & purificación , Virus de la Influenza A/genética , Virus de la Influenza B/aislamiento & purificación , Virus de la Influenza B/genética , Manejo de Especímenes/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Medios de Cultivo/química , Persona de Mediana Edad , Femenino , Adulto , MasculinoRESUMEN
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.
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Autoanticuerpos , Interferón gamma , Micosis , Talaromyces , Células TH1 , Humanos , Talaromyces/inmunología , Células TH1/inmunología , Interferón gamma/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Masculino , Adulto , Femenino , China , Micosis/inmunología , Micosis/microbiología , Persona de Mediana Edad , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/genéticaRESUMEN
BACKGROUND: Recent outbreaks of avian influenza and ongoing virus reassortment have drawn focus on spill-over infections. The increase in human infections with highly pathogenic avian influenza H5N6 virus and its high fatality rate posed a potential threat, necessitating the search for a more effective treatment. METHODS: Longitudinal clinical data and specimens were collected from five H5N6 patients after admission. All patients received antiviral treatment of either sequential monotherapy of oseltamivir and baloxavir or the two drugs in combination. Severity of illness; viral load in sputum, urine, and blood; and cytokine levels in serum and sputum were serially analyzed. FINDINGS: All patients developed acute respiratory distress syndrome (ARDS) and viral sepsis within 1 week after disease onset. When delayed oseltamivir showed poor effects, baloxavir was administered and rapidly decreased viral load. In addition, levels of IL-18, M-CSF, IL-6, and HGF in sputum and Mig and IL-18 in serum that reflected ARDS and sepsis deterioration, respectively, were also reduced with baloxavir usage. However, three patients eventually died from exacerbation of underlying disease and secondary bacterial infection. Nonsurvivors had more severe extrapulmonary organ dysfunction and insufficient H5N6 virus-specific antibody response. CONCLUSIONS: For critical human cases of H5N6 infection, baloxavir demonstrated effects on viral load and pulmonary/extrapulmonary cytokines, even though treatment was delayed. Baloxavir could be regarded as a first-line treatment to limit continued viral propagation, with potential future application in avian influenza human infections and poultry workers exhibiting influenza-like illness. FUNDING: This work was funded by the National Natural Science Foundation of China (81761128014).
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Dibenzotiepinas , Virus de la Influenza A , Gripe Aviar , Gripe Humana , Morfolinas , Piridonas , Síndrome de Dificultad Respiratoria , Sepsis , Triazinas , Animales , Humanos , Gripe Aviar/tratamiento farmacológico , Gripe Aviar/epidemiología , Oseltamivir/uso terapéutico , Subtipo H5N6 del Virus de la Influenza A , Interleucina-18/uso terapéutico , Gripe Humana/tratamiento farmacológico , Gripe Humana/epidemiología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Sepsis/tratamiento farmacológicoRESUMEN
Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.
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Background: Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. Methods: This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. Findings: Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. Interpretation: Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. Funding: This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.
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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.
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Background: Effective anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs are not only the next defense after vaccines but also the key part of establishing a multi-tiered coronavirus disease 2019 (COVID-19) prevention and control system. Previous studies had indicated that Lianhua Qingwen (LHQW) capsules could be an efficacious Chinese patent drug for treating mild to moderate COVID-19. However, pharmacoeconomic evaluations are lacking, and few trials have been conducted in other countries or regions to evaluate the efficacy and safety of LHQW treatment. So, this study aims to explore the clinical efficacy, safety, and economy of LHQW for treating adult patients with mild to moderate COVID-19. Methods: This is a randomized, double-blind, placebo-controlled, international multicenter clinical trial protocol. A total of 860 eligible subjects are randomized at a 1:1 ratio into the LHQW or placebo group to receive two-week treatment and follow-up visits on days 0, 3, 7, 10, and 14. Clinical symptoms, patient compliance, adverse effects, cost scale, and other indicators are recorded. The primary outcomes will be the measured median time to sustained improvement or resolution of the nine major symptoms during the 14-day observation period. Secondary outcomes regarding clinical efficacy will be evaluated in detail on the basis of clinical symptoms (especially body temperature, gastrointestinal symptoms, smell loss, and taste loss), viral nucleic acid, imaging (CT/chest X-ray), the incidence of severe/critical illness, mortality, and inflammatory factors. Moreover, we will assess health care cost, health utility, and incremental cost-effectiveness ratio (ICER) for economic evaluation. Discussion: This is the first international multicenter randomized controlled trial (RCT) of Chinese patent medicine for the treatment of early COVID-19 in accordance with WHO guidelines on COVID-19 management. This study will help clarify the potential efficacy and cost-effectiveness of LHQW in the treatment of mild to moderate COVID-19, facilitating decision-making by healthcare workers. Registration: This study is registered at the Chinese Clinical Trial Registry, with registration number: ChiCTR2200056727 (date of first registration: 11/02/2022).
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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.