One-year Follow-up Study Of Critically Ill COVID-19

Objective The COVID-19 pandemic crucially threatens the global public health system,leading to billions of infections and millions of deaths,as well as remaining numerous recovering patients.The critically ill COVID-19 patients were more severe compared to other types of COVID-19,but also had higher mortality and more complicated recovering patients.Our study aims to investigate the changes of living status,pulmonary function,immunological and biochemistry status during one year.Methods(1)The critically ill COVID-19 patients from Zhongnan Hospital of Wuhan University,People’s Hospital of Wuhan University,Leishenshan Hospital and Xishui People’s Hospital,Hubei,China were enrolled.Written consent was obtained from all the patients or their families.The baseline data and clinical characteristics were reviewed;(2)Follow-up interviews were performed at 3 months,6 months and 12 months after ICU discharge.These critically ill COVID-19 patients were invited to do Chest Computerized tomography,pulmonary functions tests and six-minute walking tests to investigate the long-term pulmonary changes during 1 year.(3)These critically ill COVID-19 patients Patients were followed at 3-month,6-month and 12-month after ICU discharge.Consequent blood samples were used for testing the neutralizing antibodies,TBNK lymphocyte counting and T cell subset analysis,Cytokine release from ex vivo recombinant antigen peptide stimulus to investigate the long-term changes of immunological status.(4)These critically ill COVID-19 patients Patients were followed at 3-month,6-month and 12-month after ICU discharge.Liver,renal,cardiac and coagulative functions were evaluated by testing consequent blood samples at the each follow-up time.(5)Follow-up interviews were performed at 3 months,6 months and 12 months after ICU discharge.These critically ill COVID-19 patients were evaluated for psychological disorders by the Hamilton Anxiety Scale and Zung’s self-depression Scale and cognitive function by Mini-Mental State Examination(MMSE)and Montral Cognitive Assessment(MoCA)(6)Follow-up interviews were performed at 3 months,6 months and 12 months after ICU discharge.These critically ill COVID-19 patients were interviewed for persistent symptoms,return-to-work and health-related quality of life by Medical Study 36-item Short-Form General Health Survey(SF-36)to investigate the long-term changes of living status during 1 year.Results:(1)From January 3,2020 to March 15,2020,171 critically ill COVID-19 patients were reviewed from Zhongnan Hospital of Wuhan University,Wuhan University People’s Hospital,Leishanshan Hospital and Xishui County People’s Hospital,of which 61 died and 110 survived thereafter discharge of the ICU.The overall hospital mortality rate was 35.7%.The median age is 63(IOR,55.00-71.25)years,the proportion of male patients is 62.9%;the oxygenation index(PaO2/FiO2)is 113(IQR,81-173)mmHg,the maximum lung injury score is 3.00(IQR,2.00-3.50)points.The ICU APACHE Ⅱ score is 15.00((IQR,10.50-19.00)points,and the ICU SOFA score is 4.00(IQR,3.00-6.00).(2)During 1 year follow-up,the most common imaging abnormalities in HRCT imaging are ground glass opacity(58.6%),reticular lesions(60.9%),and nodules(36.8%).The median chest CT score was 6.00(IQR,3.00-8.25)and had no significant improvement throughout the year.The CT score of intubated survivors was higher than that of non-intubated survivors.VC,FVC and FEV1 gradually returned to normal expected levels over time.There is little difference between DLCO at 3 months and 6 months,but the DLCO significantly increased to 82%(IQR,76%-97%)(P=0.015)at 12 months.FEV1/FEV did not significantly improve over time,but it was basically at the level of normal expected value;TLC and chest CT scores also had no significant difference over time,but they were always suboptimal.At 3 months,6 months,and 12 months,the average distance of 6MWT was 486 meters(IQR,428-548),526(463-584),and 533(464-575)(P=0.017),respectively.(3)All survivors were negative for SARS-COV-2 nucleic acid test(NAAT)in one-year follow-up.From 3 to 12 months,the IgG positive rate is about 90%(S-IgG 98.5%,RBD-IgG 95.5%,N-IgG 63.6%).Even after 12 months of transfer from the ICU,83.3%of patients had a positive neutralizing antibody test(positive threshold greater than>10AU/ml),although the antibody titer was 29.99AU/ml at 6 months(IQR,19.45-53.93)Decreased to 19.75AU/ml(13.13-29.84)at 12 months(P<0.001).All types of IgG antibodies remained high titers one year after leaving the ICU,and the S-IgG titer decreased from 213.06(146.74-394.43)at 6 months to 99.60AU/ml(IQR,46.85-172.12)(P<0.001);RBD-IgG decreased from 136.77(90.45-237.98 to 66.41AU/ml(IQR,27.43-123.68)at 6 months(P<0.001).After 6 months,both N-IgA and N-IgM were negative(<10AU/ml).In vitro recombinant antigen peptides(NP,S1,S2,and RBD)stimulation test found that compared with the negative control group,the separation collected at 12 months can secrete a higher level of cells Among them,the level of IL-6 increased significantly.In addition,there was no significant difference in cytokine release between antibody-positive recovery patients and antibody-negative recovery patients.After discharge of the ICU,the white blood cell count and neutrophil count of the critically ill COVID-19 patients decreased significantly,but they were all within the normal range.Critically ill COVID-19 survivors found that the absolute numbers of B cells,CD4+and CD8+cells were normal during follow-up within 1 year,and there was no significant change during the one-year follow-up.T lymphocyte function test showed that activated T cells(HLA-DR+CD3+/CD3+T cells,HLA-DR+CD8+/CD8+T cells),naive/memory CD4+T cells(CD45RA+CD4+T cells and CD45RO+CD4+T cells)The percentage is always much higher than the normal range,and the average percentage of CD28+CD8+/CD8+T is always lower than the normal range.(4)Although there was no significant difference in creatinine level at the three time points of follow-up,Cystatin C showed a significant decrease over time,and the 1.07(IQR,0.91-1.18)mg/L at the third month gradually decreased to 0.99(IQR,0.84-1.11)mg/L.The liver function,the coagulation function and the troponin returned to normal during 1 year.(5)The prevalence of depression is 18.2%to 32.8%,and the prevalence of anxiety is about 9.1%to 17.6%,which does not change over time.According to the MoCA scale,52.3%of critically ill COVID-19 patients get cognitive dysfunction at 3 months after leaving the ICU.According to the MMSE scale,some of critically ill COVID-19 patients had cognitive impairment at early period after discharge but resolved gradually over time.the percentage of cognitive dysfunction that occurs at 3 months,6 months,and 12 months It is 12.8%,2.9%and 0.(6)The most common symptoms of critically ill COVID-19 patients during 1 year are dyspnea after activities,palpitations and fatigue which are diminishing over time.48.3%of critically ill COVID-19 patients returned to work 3 months after ICU discharge,and 74.2%one year after discharge.One year later,although the general health status of the surviving COVID-19 critically ill patients has improved,it is still lower than normal.Conclusions:During the one-year follow-up of critically ill COVID-19 patients,the chest CT have not completely normalized,but the pulmonary function basically get normal except for the DLCO and residual capacity;the 6-minute walk test has basically returned to normal after 1 year.The level of neutralizing antibodies and all types of IgG of SARS-CoV-2 decreased over time,but it was still detectable within 1 year;The extrapulmonary functions return to normal.Some patients suffer from persistent anxiety and depression but their cognitive impairment has been significantly improved over time;The main left symptoms were dyspnea after activities,palpitations,and fatigue.74.2%of the surviving critically ill patients returned to work after one-year discharge from the hospital and the general health status has improved over time.