Lymphocyte Subsets And Cytokines Changes In Respiratory Infection With Adenovirus Type 7

ObjectivesAdenovirus-associated respiratory infection(RI)is characterized by high grade and prolonged fever,and a strong inflammatory response.No report characterizing HAdV-7-associated RI and its defense mechanism of organism cellular immunity has been published.To characterize adenovirus associated RI and observe defense mechanism of organism cellular immunity and correlations between it and the severity of infection in patients with human adenovirus type 7(HAdV-7)infection.We also evaluated the diagnostic performance of inflammatory markers and peripheral blood lymphocyte subset.MethodsThis retrospective study was based on data from a HAdV-7 outbreak occurring in a military training camp in China,with cases detected between January 20th and February 21th 2015.Cases with laboratory-confirmed HAdV-7 infection were enrolled in this study.Diagnoses were based on polymerase chain reaction findings from throat swab specimens collected from all patients in hospital.Demographic and clinical data,including age,sex,clinical symptoms,body temperature and maximum temperature(Tmax),vital signs,and physical examination findings,were collected for all cases.Laboratory findings,including the results of routine blood tests,blood biochemical,electrolyte,myocardial enzyme,inflammation markers,blood coagulation function and data on co-infection pathogens were recorded.Phlebotomize when patients admitted to hospital in 1-3 days.Flow cytometry analysis of lymphocytes percentage of subgroup(includingCD3+,CD4+,CD8+,NK,BC).Enzyme-linked immunosorbent assay to detect the levels of cytokines in blood in patients with(includingTNF-α,IL-2,IP-10,IL-10,IL-17A and INF-γ).Results1.A total of 218 male were diagnosed to be HAdV-7-associated RI during an outbreak.Diagnostics was performed with PCR for all the throat swab specimens collected from patients in hospital.The etiological pathogen of this outbreak was confirmed as HAdV-7.A total 82 HAdV-7-associated RI cases were enrolled.The 82 cases were classified according to the severity of adenoviral infections and there were 10 cases of severe pneumonia(AdSP),30 cases of pneumonia(AdP)and 42 cases of upper respiratory infection(URI).2.Mean age wasl8.96 years.All patients were observed high fever(39.4 ± 0.59℃).Most of them appeared flu-like symptoms such as cough(96.3%),sputum(69.5%).Gastrointestinal symptoms were also common.In physical examination,congestion of throat(93.9%)and antiadoncus(75.6%)were most common.For the complications,30%of the AdSP patients were reported with respiratory failure and decreased heart rate.Pleural effusion(20%)and hemorrhagic cystitis(20%)were also observed.3.The HRCT in all 42 URI patients were normal.In 35%of pneumonia(including AdP and AdSP)patients,it observed more than 2 lobars of lung infiltration and bilateral lung infiltration,respectively.Multiple or single lobar/segment consolidation was most common HRCT results and it was followed by ground-glass opacities.Single lobar patchy infiltration was observed in 56.7%of the patients with AdP from HRCT.More than 60%of the patients in AdSP appeared mutiple lobar or segment consolidation.4.In the blood routine results,a normal white blood cell(WBC),neutrophilia(N),lymphocyte(L)and monocyte(M)value were obtained in most patients.There was no difference among three groups.5.Biochemistry test demonstrated the level of serum ALT and AST were higher in the AdSP group.The values were gradually decreased from AdSP group to URI group,but there was no significant difference.Urea and Cr were within the normal range6.The levels of LDH,CKMB,CK and HBDH were higher in the AdSP group,but only HBDH level was significantly different between AdP group and URI group(p=0.012).7.Most PCT concentrations were within the normal range.Increased IL-6 concentrations were observed in three groups,the IL-6 concentration was significantly higher among patients with AdSP than among those with AdP(p=0.005)and URI(p = 0.042).The mean ESR of patients with URI was within the normal range,but that of patients with AdP was higher than normal(p = 0.008).Mean ESR was higher in patients with AdSP than in those with AdP.Reduced PA level was correlated negatively with increased CRP level in patients with AdP(r =-0.536,p = 0.003).Tmax was correlated positively with the serum PCT concentration(r = 0.558,p = 0.001)and negatively with the PA concentration(r =-0.306,p = 0.005).No correlation was observed with the IL-6 or CRP concentration,or ESR.8.Although in some cases,the PT in three groups was longer than the normal value,the mean time was still in the normal reference range.FDP and DD in AdSP group were increased significantly.The APTT in AdSP group was significantly different from the value in AdP group(p=0.011)and URI group(p=0.025).It observed no association between duration and APTT,duration and PT value determined in different time.9.The mean value of CD3+ in AdSP was significantly different with the URI(p=0.002)and AdP(p=0.021).Mean value of CD8+ percentage and CD4+/CD8+ratio in AdSP were lower than that of in AdP.Both of them were lower than URI.NK in RI was also significantly decreased than normal.With the aggravation of the disease,NK decline more obviously.B lymphocytes percentage in three groups was higher than the normal reference value.The value was significantly different from that of in URI(p=0.002),as well as in AdP(p=0.016).There was a negative correlation(r=-0.616,p>0.050)between CD4+ and ALB level in AdSP,which was not statistically significant.It obtained a significantly positive correlation between NK and ALB level(r=0.449,p<0.001)in URI.Serum phosphorus levels were positively correlated with CD8+ value and the correlation coefficient was 0.421 in the URI,which was also significant(p<0.001).CD3+ and NK have better performance in differentiating of AdSP to AdP.10.Mean INF-y in AdP and AdSP were significantly lower than URI.TNF-a in AdSP was significantly higher than URI(p<0.001)and AdP(p<0.001).IL-10 was decline with the illness aggravating gradually.IL-10 was highest in the URI group.There was statistically significant difference between AdPand URI(p=0.034).IL-17A reduced gradually as HAdV-7 infection condition of aggravating.When compared AdP(p<0.001)and AdSP(p<0.001)with URI,all had significantly differences.IL-2 in AdSPwere significantly higher than URI(p<0.001)and AdP(p<0.001).Mean IP-10 in AdSP significantly higher than URI and had significantly differences(p=0.042).Conclusion1.HAdV-7 respiratory infections in the military camp have severe clinical symptoms,high ratio of complicated pneumonia and easy development to severe or critically ill.lt is an important public health problem.2.HAdV-7 associated severe pneumonia complicated with respiratory failure,cardiac dysfunction,electrolyte disorder,hemorrhagic cystitis,appear multiple system dysfunction.3.Lung infiltration and consolidation are common in HRCT.Multiple or single lobar/segment consolidation was most common in AdSP.AdSP has been progressed very quickly after onset.4.Strong inflammatory responses are observed in patients with HAdV-7 associated RI.HAdV-7 infection can typically result in elevated ESR,CRP and IL-6 level,reduce PA.CRP and PA has negative correlation in patients with HAdV-7-associated RI.5.PA may act as a negative protein.With the aggravation of the HAdV-7infection,its level is gradually reduced.IL-6 is associated with severity of the illness,IL-6 plays an important role in the pathogenesis of HAdV-7 respiratory infection.6.HAdV-7 infection can lead to blood coagulation disorders.7.Cellular immunity plays an important role in compete with HAdV-7 respiratory infection that lead body’s immune system damage and imbalance of immune state.CD3 +,CD4 + and NK ratio decreased,B lymphocyte ratio increases.Monitoring lymphocyte subgroup has important value for the judgment about the illness occurrence,development and severity.8.Cytokines also play an important role in immune response to HAdV-7 infections.Lower INF-γ,IL-10 and IL-17A,higher IP-10 was observed in AdSP.Various cytokines regulate each other,influence each other and form a complex network of cytokines.9.TNF-a,IL-2 and IL-10 are correlated with the HAdV-7 infection severity.IL-10 levels significantly decreased with the aggravation of the HAdV-7infection.TNF-a and IL-2 increased significantly.They can help for judging HAdV-7 respiratory tract infection disease severity.10.In predictin AdSP risk,PA,CD3+ cells and IL-10 have great clinical value.They can help to achieve early diagnosis and treatment,reducing the incidence of AdSP.