Heterozygous CARD9 mutation favors the development of allergic bronchopulmonary aspergillosis

Background:Previous research demonstrated that a homozygous mutation of g.136372044G>A(S12N)in caspase recruitment domain family member 9(CARD9)is critical for producing Aspergillus fumigatus-induced(Af-induced)T helper 2(T_(H)2)-mediated responses in allergic bronchopulmonary aspergillosis(ABPA).However,it remains unclear whether the CARD9^(S12N)mutation,especially the heterozygous occurrence,predisposes the host to ABPA.Methods:A total of 61 ABPA patients and 264 controls(including 156 healthy controls and 108 asthma patients)were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA.A series of in vivo and in vitro experiments,such as quantitative real-time polymerase chain reaction,flow cytometry,and RNA isolation and quantification,were used to illuminate the involved mechanism of the disease.Results:The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients,regardless of Aspergillus sensitivity.Relative to healthy controls without relevant allergies,the mutation of p.S12N was associated with a significant risk of ABPA(OR:2.69 and 4.17 for GA and AA genotypes,P=0.003 and 0.029,respectively).Compared with patients with asthma,ABPA patients had a significantly higher heterozygous mutation(GA genotype),indicating that p.S12N might be a significant ABPA-susceptibility locus(aspergillus sensitized asthma:OR:3.02,P=0.009;aspergillus unsensitized asthma:OR:2.94,P=0.005).The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9^(S12N),which contributes to its functional alterations to facilitate Af-induced T_(H)2-mediated ABPA development.In terms of mechanism,Card9 wild-type(Card9^(WT))expression levels decreased significantly due to Af-induced decay of its messenger RNA compared to the heterozygous Card9 S12N.In addition,ABPA patients with heterozygous CARD9^(S12N)had increased Af-induced interleukin-5 production.Conclusion:Our study provides the genetic evidence showing that the heterozygous mutation of CARD9^(S12N),followed by allele expression imbalance of CARD9^(S12N),facilitates the development of ABPA.

Pathogen evolution, prevention/control strategy and clinical features of COVID-19: experiences from China

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was reported at the end of 2019 as a worldwide health concern causing a pandemic of unusual viral pneumonia and many other organ damages,which was defined by the World Health Organization as coronavirus disease 2019(COVID-19).The pandemic is considered a significant threat to global public health till now.In this review,we have summarized the lessons learnt during the emergence and spread of SARS-CoV-2,including its prototype and variants.The overall clinical features of variants of concern(VOC),heterogeneity in the clinical manifestations,radiology and pathology of COVID-19 patients are also discussed,along with advances in therapeutic agents.

Coronavirus disease 2019(COVID-19):a clinical update

Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has posed a significant threat to global health.It caused a total of 80868 confirmed cases and 3101 deaths in Chinese mainland until March 8,2020.This novel virus spread mainly through respiratory droplets and close contact.As disease progressed,a series of complications tend to develop,especially in critically ill patients.Pathological findings showed representative features of acute respiratory distress syndrome and involvement of multiple organs.Apart from supportive care,no specific treatment has been established for COVID-19.The efficacy of some promising antivirals,convalescent plasma transfusion,and tocilizumab needs to be investigated by ongoing clinical trials.

Atrial of arbidol hydrochloride in adults with COVID-19

Background: To date, there is no effective medicine to treat coronavirus disease 2019 (COVID-19), and the antiviral efficacy of arbidol in the treatment for COVID-19 remained equivocal and controversial. The purpose of this study was to evaluate the efficacy and safety of arbidol tablets in the treatment of COVID-19.Methods: This was a prospective, open-label, controlled and multicenter investigator-initiated trial involving adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients were stratified 1:2 to either standard-of-care (SOC) or SOC plus arbidol tablets (oral administration of 200 mg per time, three times a day for 14 days). The primary endpoint was negative conversion of SARS-CoV-2 within the first week. The rates and 95% confidential intervals were calculated for each variable.Results: A total of 99 patients with laboratory-confirmed SARS-CoV-2 infection were enrolled;66 were assigned to the SOC plus arbidol tablets group, and 33 to the SOC group. The negative conversion rate of SARS-CoV-2 within the first week in patients receiving arbidol tablets was significantly higher than that of the SOC group (70.3% [45/64]vs. 42.4% [14/33];difference of conversion rate 27.9%;95% confidence interval [CI], 7.7%-48.1%;P=0.008). Compared to those in the SOC group, patients receiving arbidol tablets had a shorter duration of clinical recovery (median 7.0 daysvs. 12.0 days;hazard ratio [HR]: 1.877, 95% CI: 1.151-3.060,P=0.006), symptom of fever (median 3.0 daysvs. 12.0 days;HR: 18.990, 95% CI: 5.350-67.410,P<0.001), as well as hospitalization (median 12.5 daysvs. 20.0 days;P<0.001). Moreover, the addition of arbidol tablets to SOC led to more rapid normalization of declined blood lymphocytes (median 10.0 daysvs. 14.5 days;P > 0.05). The most common adverse event in the arbidol tablets group was the elevation of transaminase (5/200, 2.5%), and no one withdrew from the study due to adverse events or disease progression.Conclusions: SOC plus arbidol tablets significantly increase the negative conversion rate of SARS-CoV-2 within the first week and accelerate the recovery of COVID-19 patients. During the treatment with arbidol tablets, we find no significant serious adverse events.

Executive summary of Chinese expert consensus for topical application of anti-microbial agents for lower respiratory tract infection in adults

In recent years,with the increased prevalence of multi-drug resistant(MDR)bacterial infection and chronic pulmonary infection,the topical application of anti-microbial agents,mainly inhaled antibiotics,has come back to clinical practice.Several formulations for nebulization and dry powder inhaler(DPI)have been approved for inhaled anti-infective therapy.Meanwhile,evidence and experience have been accumulated in the use of anti-microbial agents delivered via airway.However,the available studies in this field are heterogenous in the study population,drug delivery route and dosages.The efficacy and safety of inhaled anti-infective therapy in various types of lower respiratory tract infections(LRTIs)need to be evaluated.Moreover.

A pilot study on Paxlovid therapy for hemodialysis patients with severe acute respiratory syndrome coronavirus 2 infections

We aimed to investigate the safety and efficacy of nirmatrelvir/ritonavir(Paxlovid)therapy for hemodialysis-dependent patients with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Thirteen hemodialysis patients infected with the Omicron variant of SARS-CoV-2 from April 3 to May 30,2022,were recruited.Laboratory parameters and chest CT(computed tomography)imaging were analyzed.The treatment group included six patients who received 150 mg/100 mg of Paxlovid orally once daily for 5 days,whereas the control group included seven patients who received basic treatment.No serious adverse reactions or safety events were recorded.Four control patients progressed to moderate disease,and none in the treatment group showed progression of chest CT findings(P<0.05).Paxlovid therapy tended toward early viral clearance and low viral load on Day 8.Moreover,83.3%of the patients in the treatment group and 57.1%of the patients in the control group turned negative within 22 days.In the Paxlovid treatment group,we found significantly increased levels of lymphocytes(P=0.03)and eosinophils(P=0.02)and decreased levels of D-dimer on Day 8 compared with those on Day 1.Paxlovid therapy showed a potential therapeutic effect with good tolerance in hemodialysis patients.The optimal dose and effectiveness evaluation must be further investigated in a largeer cohort.