Effect Of Convalescent Plasma Therapy On Convid-19 And The Role Of Immunogenetics In COVID-19

BackgroundCoronavirus disease-2019(COVID-19)caused by SARS-CoV-2 has had a significant negative impact on societies,economies worldwide,posing a serious threat to human lives.In the early stages of the outbreak,effective drugs and vaccines were lacking,and convalescent plasma is a potential treatment option for patients with COVID-19.However,further data from randomized clinical trials are required.The early identification of high-risk patients after infection with SARS-CoV-2 is of great significance for improving the therapeutic effects of the disease.The progression of a patient’s disease is affected by many factors,such as their own immune response ability,among which the role of patient HLA-KIR receptor matching in COVID-19 progression is still unclear.ObjectiveThis study aimed to evaluate the efficacy and safety of convalescent plasma therapy in patients with severe and critical COVID-19.To investigate the association between HLA,KIR,or HLA-KIR receptor-ligand pairs and the severity of COVID-19.MethodsAn open-label,multicenter,randomized clinical trial was performed at seven medical centers in Wuhan,China,from February 14,2020,to April 1,2020,with a final followup of April 28,2020.A total of 103 patients with laboratory-confirmed COVID-19 with severe(respiratory distress and/or hypoxemia)or critical illness(shock,organ failure,or need for mechanical ventilation)were enrolled in the trial.The trial was planned to recruit 200 patients and terminated early after recruiting 103 patients.Convalescent plasma combined with conventional therapy(n=52)was compared with conventional therapy alone(control group,n=51)and stratified by disease severity.The primary outcome was the time to clinical improvement within 28 days,defined as patient discharged alive or a 2-point reduction on a 6-point disease severity scale(scale from 1[discharge]to 6[death]).Secondary outcomes included 28-day mortality,time to discharge,and the proportion of viral polymerase chain reaction(PCR)results that turned from positive to negative within 72 h.Samples of 305 severe and critical COVID-19 patients(40 critical and 265 severe)were collected from Zhongnan Hospital of Wuhan University and 597 healthy controls to investigate the possible association of HLA alleles,KIR genes,and KIR/HLA ligand combination with COVID-19 disease progression.HLA typing was performed using nextgeneration sequencing(NGS),and HLA allele frequency association analysis and heterozygosity analysis were performed using pyHLA software.Polymerase chain reaction-sequence specific probe(PCR-SSO)and multiplex polymerase chain reactionsequence specific primer amplification(PCR-SSP)techniques were used for 305 COVID19 patients and 500 healthy controls for KIR genotyping and to analyze KIR/HLA ligand combination relationships.Statistical analysis,including the chi-square test,was performed using spss23.0 software.ResultsOf the 103 patients who were randomized(median age,70 years;60[58.3%]male),101(98.1%)completed the trial.Clinical improvement occurred within 28 days in 5 1.9%(27/52)of the convalescent plasma group vs.43.1%(22/51)of the control group(difference,8.8%[95%CI,-10.4%to 28.0%];hazard ratio[HR],1.40[95%CI,0.792.49];P=.26).Among those with severe disease,the primary outcome occurred in 91.3%(21/23)of the convalescent plasma group vs.68.2%(15/22)of the control group(HR,2.15[95%CI,1.07-4.32];P=.03).Among those with life-threatening disease,the primary outcome occurred in 20.7%(6/29)of the convalescent plasma group vs.24.1%(7/29)of the control group(HR,0.88[95%CI,0.30-2.63];P=.83)(P for interaction=.17).There was no significant difference in 28-day mortality(15.7%vs.24.0%;OR,0.65[95%CI,0.29-1.46];P=.30)or time from randomization to discharge(51.0%vs.36.0%discharged by day 28;HR,1.61[95%CI,0.88-2.93];P=.12).Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 h in 87.2%of the convalescent plasma group vs.37.5%of the control group(OR,11.39[95%CI,3.9133.18];P<.001).Two patients in the convalescent plasma group experienced adverse events within hours after transfusion,which improved with supportive care.In the study of HLA,KIR,and disease progression,it was observed that the frequency distribution of HLA-B*46:01(OR=1.5[95%CI,1.1-2.0],P=0.04)and its haplotype HLA-A*02:07-C*01:02-B*46:01-DRB1*09:01-DQB1*03:03(OR=2.01[95%CI,1.22-3.31],P=0.007)was significantly higher in COVID-19 severe and critical patients than in healthy controls.Homozygosity of HLA-B*40:01,B*46:01,DRB1*09:01,DQA1*01:02,DQB1*03:03 alleles is associated with severe or critical COVID-19.KIR2DL2(OR=2.94[95%CI,1.36-6.36],P=0.006)was associated with progression to the critical stage.ConclusionFor critical and severe COVID-19 patients,conventional therapy combined with recovery plasma therapy did not result in a statistically significant improvement in the time to clinical improvement within 28 days compared to standard therapy alone.Interpretation is limited by the early termination of the trial,which may have been underpowered to detect clinically important differences.In the Chinese population,high-frequency HLA alleles and haplotypes are associated with the severity of disease progression in COVID-19 patients.KIR2DL2 also affects disease severity in patients with COVID-19.From an immunogenetic perspective,the risk of critical illness after SARS-CoV-2 infection in the Chinese population may be higher than in Caucasians and requires more attention to early treatment...